Gene expression profile algorithm and test for determining prognosis of prostate cancer.

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The undersigned of this title does so based on the provisions of articles 6 fraction III, 7 BIS 2 and 59 of the Industrial Property Law; articles 1^S, 3^S fraction V Subsection a), sub Subsection I), 4^S and 12^s sections I and III of the Regulations of the Mexican Institute of Industrial Property; articles 1^S, 3^S, 4⁵, 5^S fraction V Subsection a), sub Subsection I), 16 fractions I and III and 30 of the Organic Statute of the Mexican Institute of Industrial Property; one^S, 3⁵ and 5^S Subparagraph a) and the second to last paragraph of the Agreement that delegates powers to the Deputy General Directors, Coordinator, Divisional Directors, Regional Office Holders, Divisional Deputy Directors, Departmental Coordinators and other subordinates of the Mexican Institute of Industrial Property.

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DIVISIONAL SUB-DIRECTOR OF PATENT FUND EXAMINATION BIOTECHNOLOGICAL, PHARMACEUTICAL AND CHEMICAL AREAS

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EMELIA HERNANDEZ PRIEGO

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MX / 2019/60746 ® »58 *« W⁵

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Date:

October 2012

Number:

61/713,734

GENE EXPRESSION AND TEST PROFILE ALGORITHM FOR

DETERMINE THE PROSTATE CANCER PROGNOSIS

Field of the Invention

The present description refers to molecular diagnostic assays that provide information regarding gene expression profiles to determine prognostic information for cancer patients. Specifically, the present description provides an algorithm comprising genes, or co-expressed genes, the expression levels of which can be used to determine the likelihood that a patient with prostate cancer will experience a positive or negative clinical outcome.

Background of the Invention

The introduction of the prostate specific antigen (PSA) classification in 1987 has led to the diagnosis and aggressive treatment of many cases of indolent prostate cancer that would never have been clinically significant or caused death. The reason for this is that the natural history of prostate cancer is unusual among the malignancies in which most cases are indolent and even if left untreated they would not progress during the course of a man's life to cause suffering or

Ref: 282301 half of men develop invasive prostate cancer during their lifetime (as detected by autopsy studies) (B. Halpert et al., Cancer 16: 737-742 (1963); B. Holund, Scand J Urol Nephrol 14: 29-35 (1980); S. Lundberg et al., Scand J Urol Nephrol 4: 93-97 (1970); M. Yin et al., J Urol 179: 892-895 (2008)), only 17% will be diagnosed with prostate cancer and only 3% will die as a result of prostate cancer. Cancer Facts and Figures. Atlanta, GA: American Cancer Society (2010); JE Damber et al., Lancet 371: 17101721 (2008).

However, currently, more than 90% of men who are diagnosed with prostate cancer, even with low-risk prostate cancer, are treated with either immediate radical prostatectomy or definitive radiation therapy. MR Cooperberg et al., J Clin Oncol 28: 1117-1123 (2010); MR Cooperberg et al., J Clin Oncol 23: 8146-8151 (2005). Radiation therapy and surgery reduce the risk of recurrence and death of prostate cancer (AV D'Amico et al., Jama 280: 969-974 (1998); M Han et al., Urol Clin North Am 28: 555-565 ( 2001); WU Shipley et al., Jama281: 1598-1604 (1999); AJ Stephenson et al., J Clin Oncol 27: 43004305 (2009)), however estimates of the number of men to be treated to prevent a death from Prostate cancer ranges from 12 to 100. To Bill-Axelson et al., J Nati Cancer Inst 100: 1144-1154 (2008); J

Hugosson et al., Lancet Oncol 11: 725-732 (2010); LH Klotz et al., Can J Urol 13 Suppl 1: 48-55 (2006); S

Loeb et al., J Clin Oncol 29: 464-467 (2011); Fh

Schroder et al., N Engl J Med 360: 1320-1328 (2009). This over-treatment of prostate cancer has a cost of money and toxicity. For example, the majority of men who undergo radical prostatectomy suffer from incontinence and impotence as a result of the procedure (MS Litwin et al., Cancer 109: 2239-2247 (2007); MG

Sanda et al., N Engl J Med 358: 1250-1261 (2008), and as many as 25% of men regret their choice of treatment for prostate cancer. FR Schroeck et al., Eur Urol 54: 785-793 (2008).

One of the reasons for prostate cancer over-treatment is the lack of adequate prognostic tools to distinguish men who need immediate definitive therapy from those who are appropriate candidates to postpone immediate therapy and instead undergo active surveillance. For example, of men who appear to have low-risk disease based on the results of clinical staging, treatment PSA, and Gleason biopsy record, and have been managed with active surveillance protocols, 30-40 % experience disease progression (diagnosed by PSA elevation, an increased Gleason record in repeat biopsy, or clinical progression) during the first few years of follow-up, and some of them may have missed the opportunity for curative therapy. HB Carter et al., J Urol 178: 2359-2364 and discussion 23642355 (2007); MA Dalí 'Era et al., Cancer 112: 26642670 (2008); L Klotz et al., J Clin Oncol 28: 126131 (2 010). Also, of the men who appear to be candidates for active surveillance, but those who undergo immediate prostatectomy anyway, 30-40% are in surgery because they have a higher risk than expected as defined by having high grade (Gleason record of 3 + 4 or higher) or confined not to organs (extracapsular extension (ECE) or seminal vesicle complication (SVI)). SL et al., J Urol 181: 1628-1633 and discussion 1633-1624 (2009); CR Griffin et al., J Urol 178: 860-863 (2007); PW Mufarrij et al., J Urol 181: 607-608 (2009).

0 Estimates of risk of recurrence in treatment decisions in prostate cancer are currently based primarily on PSA levels and / or clinical tumor stage. Although the clinical tumor stage has shown that it has a significant association with the outcome, sufficient to be included in the pathology reports, the College of American Pathologists Consensus Statement noted that there are variations in the procedure to the acquisition, interpretation, report and analysis of this information. C. Compton, et al., Arch Pathol Lab Med 124: 979-992 (2000). As a consequence, existing pathological staging methods have been criticized for lack of reproductive capacity and therefore can provide imprecise estimates of risk for individual patients.

Brief Description of the Invention

This application describes molecular assays that involve the measurement of the level (s) of expression of one or more genes or subsets of genes from a biological sample obtained from a patient with prostate cancer, and analysis of the measured expression levels to provide information regarding the probability of a clinical outcome. For example, the probability of a clinical outcome can be described in terms of a quantitative record based on intervals without clinical or biochemical recurrences, total survival, prostate cancer specific survival, eclipsed / increased biopsy for radical prostatectomy, or presence of high-grade disease or confined not to organ in radical prostatectomy.

In addition, this application describes molecular assays that involve measuring the level (s) of expression of one or more genes or subsets of genes from a biological sample obtained to identify a risk classification for a patient with prostate cancer. For example, patients can be stratified using the level (s) of expression of one or more genes, positively or negatively, with the positive clinical outcome of prostate cancer, or with a prognostic factor. In an exemplary mode, the forecast factor is the Gleason record.

The present invention provides a method for predicting the likelihood of a clinical outcome for a patient with prostate cancer that comprises determining a level of one or more RNA transcripts, or an expression product thereof, in a biological sample that It contains tumor cells obtained from the patient, wherein the RNA transcript or its expression product is selected from 81 shown in Figure 1 and listed in Tables 1A and IB. The method comprises assigning the one or more RNA transcripts, or an expression product thereof, to one more gene groups selected from a group of cellular organization genes, group of basal epithelial genes, a group of response genes from tension, a group of androgen genes, a group of stromal response genes and a group of proliferation genes. The method further comprises calculating a quantitative record for the patient by weighing the level of the one or more RNA transcripts or an expression product thereof, by their contribution to a clinical outcome and predicting the likelihood of a clinical outcome for the patient based in the quantitative record. In one embodiment of the invention, an increase in the quantitative record correlates with an increased probability of a negative clinical outcome.

In a particular embodiment, the one or more RNA transcripts, or an expression product thereof is selected from BIN1, XGF1, C7, GSN, DES, TGFB1I1, TPM2, VCL, FLNC, ITGA7, COL6A1, PPP1R12A, GSTM1, GSTM2, PAGE4, ​​PPAP2B, SRD5A2, PRKCA, IGFBP6, GPM6B, OLFML3, HLF, CYP3A5, KRT15, ​​KRT5, LAMB3, SDC1, DUSP1, EGFR1, FOS, JUN, EGR3, GADD45B, ZNKL, S4KP, FAM, BGN, THBS2, INHBA, COL1A1, COL3A1, COL1A2, SPARC, COL8A1, COL4A1, FN1, FAP, COL5A2, CDC20, TPX2, UBE2T, MYBL2, and CDKN2C. BIN1, IGF1, C7, GSN, DES, TGFB1I1, TPM2, VCL, FLNC, ITGA7, COL6A1, PPP1R12A, GSTM1, GSTM2, PAGE4, ​​PPAP2B, SRD5A2, PRKCA, IGFBP6, GPM6B, OLFML3, and HLF genes are assigned to HLFML3 group of cellular organization. CYP3A5, KRT15, ​​KRT5, LAMB3, and SDC1 are assigned to the basal epithelial gene group. DUSP1, EGFR1, FOS, JUN, EGR3, GADD45B, and ZFP36 are assigned to the group of stress response genes. FAM13C, KLK2, AZGP1, and SRD5A2 are assigned to the androgen gene group. ASPN, SFRP4, BGN, THBS2, INHBA, COL1A1, COL3A1, COL1A2, SPARC, COL8A1, COL4A1, FN1, FAP and COL5A2 are assigned to the stromal response gene group. CDC20, TPX2, UBE2T,

MYBL2, and CDKN2C are assigned to the proliferation gene group. The method may further comprise determining the level of at least one RNA transcript, or an expression product thereof, selected from STAT5B, NFAT5, AZGP1,

ANPEP, IGFBP2, SLC22A3, ERG, AR, SRD5A2, GSTM1, and GSTM2.

In one embodiment of the invention, the level of one or more RNA transcripts or an expression product thereof, of each of the stromal response gene group and the cell organization gene group are determinative. In another embodiment, the level of one or more RNA transcripts, or the expression products thereof, of each of the stromal response gene group and the PSA gene group are determined. Additionally, the level of one or more RNA transcripts, or the expression products thereof, of the cell organization gene group and / or proliferation gene group can be determined. In this modality, the gene (s) being tested for the stromal response gene group can be selected from ASPN, BGN, COL1A1, SPARC, FN1, COL3A1, COL4A1, INHBA, THBS2, and

SFRP4; the gene (s) that are tested from the androgen gene group can be selected from FAM13C and KLK2; The gene (s) that are tested from the group of cellular organization genes can be selected from FLNC, GSN, GSTM2, IGFBP6, PPAP2B, PPP1R12A, BIN1, VCL, IGF1, TPM2, C7, and

GSTM1; and the gene (s) being tested for the proliferation gene group can be selected from TPX2, CDC20, and

MYBL2.

In a particular embodiment, RNA transcripts, or their expression products, are selected from BGN, COL1A1, SFRP4, FLNC, GSN, TPM2, TPX2, FAM13C, KLK2, AZGP1, GSTM2, and SRD5A2. BGN, C0L1A1, and SFRP4 are assigned to the stromal response gene group; FLNC, GSN, and TPM2 are assigned to the group of cellular organization genes; and FAM13C and KLK2 are assigned to the androgen gene group. The level of RNA transcripts, or their expression products, which comprise at least one of the gene groups selected from the stromal response gene group, cell organization gene group, and androgen gene group, can be determine for the method of the invention. In any of the embodiments, the androgen gene group may further comprise AZGP1 and SRD5A2.

In addition, the level of any of the gene combinations shown in Table 4 can be determined. For example, the RSO model in Table 4 comprises determining the levels of the RNA transcripts, or the gene expression products thereof, of ASPN, BGN, COL1A1, SPARC,

FLNC, GSN, GSTM2, IGFBP6, PPAP2B, PPP1R12A, TPX2, CDC20,

MYBL2, FAM13C, KLK2, STAT5B, and NFAT5. Additionally, any of the algorithms shown in Table 4 can be used to calculate the quantitative record for the patient.

Brief Description of the Figures

<td>The figure</td><td> 1</td><td>it is</td><td>a</td><td>dendogram</td><td>what</td><td>i represents</td><td>the</td>

<td>Association of</td><td>the</td><td> 81</td><td colspan="3">selected genes</td><td>of the study</td><td>from</td>

<td colspan="2">Identification of</td><td>gen.</td><td></td><td></td><td></td><td></td><td></td>

<td colspan="2">The figures</td><td>2A,</td><td>2B,</td><td>2C, 2D and</td><td>2E</td><td>they are graphic</td><td>from</td>

<td>dispersion that</td><td colspan="2">show</td><td>the</td><td>comparison</td><td>from</td><td>The expression</td><td>of the</td>

normalized gene (Cp) for matching samples from each patient where the x-axis in the gene expression of the primary Gleason pattern RP (PGP) sample and the y-axis is the expression of the biopsy sample gene (BX). Figure 2A: All ECM genes (stromal response); Figure 2B: All migration genes (cellular organization); Figure 2C: All proliferation genes; Figure 2D: PSA (androgen); Figure 2E: other genes from the list of 81 genes that are not found within any of these four gene groups.

Figures 3A, 3B, 3C and 3D are interval graphs of the expression of individual genes within each gene group in biopsy (BX) and PGP RP samples. Figure 3A: All NDEs (stromal response); Figure 3B: All migration genes (cellular organization); Figure 3C: All proliferation genes; 3D Figure: other genes of 81 genes that are not found within any of the gene groups.

Figure 4 is a schematic illustration of the method of select-stacked groups used to identify genes or co-expressed.

Figures 5A, 5B and 5C show examples of selected and stacked groups. Figure 5A is an example of a graph that is not a select group; Figure 5B is an example of a select group; Figure 5C is an example of a select group but is not a maximum select group.

Figure 6 is a graph showing two maximum selected groups: 1-2-3-4-5 and 1-2-3-4-6.

Figure 7 schematically illustrates the stacking of two maximum select groups.

Figure 8 is a graph showing that the RS27 and CAPRA risk groups predict freedom from high-grade disease or not confined to organs.

Figure 9 is a graph showing that the RS27 and AUA risk groups predict freedom from high-grade disease or not confined to organs.

Figure 10 is a graph showing the time to clinical recurrence of patients with low PTEN and normal PTEN from the gene identification study.

Figure 11 is a graph showing the time to clinical recurrence of patients in the gene identification study stratified in low / normal PTEN and negative / positive TMPRSS-ERG.

Detailed description of the invention

DEFINITIONS

Unless defined otherwise, the technical and scientific terms used herein have the same meaning as is commonly understood by a person of ordinary experience in the field to which this invention pertains. Singleton et al., Dictionary of Microbiology and Molecular Biology 2nd ed. J. Wiley &amp; Sons (New York, NY 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley &amp; Sons (New York, NY 1992), provide an expert in the field with a general guide for much of the terms used in this application.

A person skilled in the field will recognize many methods and materials similar or equivalent to those described herein, which can be used in the practice of the present invention. In fact, the present invention is in no way limited to the methods and materials described herein. For purposes of the invention, the following terms are defined below.

The terms tumor and lesion as used herein, refer to all neoplastic cell growth and proliferation, whether malignant or benign, and all precancerous and cancerous cells and tissues. Those skilled in the field will know that a sample of tumor tissue can comprise multiple biological elements, such as one or more cancer cells, partial or fragmented cells, multi-stage tumors, which surround tissue that appears histologically normal and / or macro tissue or dissected.

The terms cancer and cancerous refers to or describes the physiological condition in mammals that is typically characterized by unregulated cell growth. Examples of cancers in the present description include urogenital tract cancer, such as prostate cancer.

As used herein, the term prostate cancer is used in the broadest sense and refers to all stages and all forms of cancer that arise from the tissue of the prostate gland.

Cancer staging helps a doctor assess how far the disease has progressed and plan a treatment for the patient. Staging can be done clinically (clinical staging) by physical examination, blood tests or response to radiation therapy, and / or pathologically based (pathological staging) in surgery, such as radical prostatectomy. □ θ according to the tumor staging system, node, metastasis (TNM) of the American Joint Committee on Cancer (AJCC), AJCC Cancer Staging Manual (7th

Ed., 2010), the various stages of prostate cancer are defined as follows: Tumor: Ti: clinically non-evident tumor not palpable or visible by imaging, Aunt: incidental histological discovery of the tumor in 5% or less of the tissue resected, Tlb: incidental histological discovery of the tumor in more than 5% of the resected tissue, Tic: tumor identified by needle biopsy; T2: tumor confined within the prostate, T2a: the tumor involves one half of a lobe or less, T2b: the tumor involves more than half of a lobe, but not both lobes, T2c: the tumor involves both lobes; T3: the tumor extends through the prosthetic capsule, T3a: extracapsular extension (unilateral or bilateral), T3b: the tumor invades the seminal vesicle (s); T4: The tumor is fixed or invades adjacent structures other than seminal vesicles (bladder neck, external sphincter, rectum, lifting muscles, or pelvic wall). Generally, a clinical stage T (cT) is TI or T2 and the pathological stage T (pT) is T2 or higher. Node: NO: non-regional lymph node metastasis; Ni: metastases in regional lymph nodes. Metastasis: M0: non-distant metastasis; MI: distant metastasis present.

The Gleason classification system is used to help evaluate the prognosis of men with prostate cancer. Together with other parameters, it is incorporated into a prostate cancer staging strategy, which predicts prognosis and helps guide therapy. A record or grade of Gleason is provided to prostate cancer based on its microscopic appearance. Tumors with a low Gleason registry typically develop slowly enough that they may not pose a significant threat to patients in their lifetime. These patients are monitored (waiting for observation or active surveillance) over time. Cancers with a higher Gleason record are more aggressive and have a worse prognosis, and these patients are usually treated with surgery (for example, radial prostatectomy) and, in some cases, therapy (for example, radiation, hormones, ultrasound , chemotherapy). Gleason records (or sums) comprise grades of the two most common tumor patterns. These patterns are referred to as Gleason 1-5 patterns, with pattern 1 being the most distinct. Most have a mix of patterns. To obtain a Gleason record or grade, the dominant pattern is added to the second most prevalent pattern to obtain a number between 2 and 10. Gleason Grades include: G1: well differentiated (light anaplasia) (Gleason 2-4); G2: moderately differentiated (moderate anaplasia) (Gleason 5-6); G3-4: poorly differentiated / undifferentiated (marked anaplasia) (Gleason 7-10).

Stage groupings: Stage I: Aunt NO M0 Gl; Stage II:

(Aunt NO MO G2-4) or (Tlb, c, TI, T2, NO MO any G); Stage III: T3 NO MO any G; Stage IV: (T4 NO MO any G) or (any T NI MO any G) or (any T any N MI any G).

The term "increase" as used herein refers to an increase in the degree of Gleason determined from biopsy to the degree of Gleason determined from radical prostatectomy (RP). For example, the increase includes a change in the degree of Gleason from 3 + 3 or 3 + 4 in the biopsy to 3 + 4 or greater in RP. Significant increase or increase 2 as used herein, refers to a change in the Gleason grade of 3 + 3 or 3 + 4 determined from the biopsy at 4 + 3 or greater, or seminal vesicle complication (SVI, by its acronym in English), or extracapsular complication (ECE) as determined by RP.

The term high grade as used herein refers to the Gleason record of&gt; = 3 + 4 or&gt; = 4 + 3 in RP. The term low grade as used herein refers to a 3 + 3 Gleason record in RP. In a particular embodiment, high-grade disease refers to a Gleason record of at least 4 major patterns, 5 minor patterns, or 5 tertiary patterns.

The term reclassification as used herein refers to an increase in the tumor stage of the biopsy to the tumor stage in RP. For example, reclassification is a change in the tumor stage of the clinical stage TI or T2 in the pathological stage T3 biopsy in RP.

The term "non-organ confined disease" as used herein refers to having the pathological stage T3 disease in RP. The term confined to organ as used herein refers to the pathological stage pT2 in RP.

The term adverse pathology as used herein refers to a high-grade disease as defined in the foregoing, or disease not confined to the organ as defined in the foregoing. In a particular modality, adverse pathology refers to prostate cancer with a Gleason record of&gt; = 3 + 4 or&gt; = 4 + 3 or T3 pathological stage.

In another embodiment, the term "high-grade or non-organ confined disease" refers to prostate cancer with a Gleason record of at least 4 major patterns, 5 minor patterns, or 5 tertiary patterns, or pathological stage.

T3

As used herein, the terms " active vigil" and "waiting under observation" mean closely monitoring the condition of a patient without giving any treatment until symptoms occur or change. For example, in prostate cancer, waiting on observation is usually used in older men with other medical problems and early stage disease.

As used herein, the term "surgery" applies to surgical methods performed for the removal of cancerous tissue, including pelvic lymphadenectories, radical prostatectomy, transurethral resection of the prostate (TURP), excision, dissection, and tumor biopsy / removal. Tumor tissue or sections used for gene expression analysis may have been obtained by any of these methods.

As used herein, the term "biological sample containing cancer cells" refers to a sample comprising tumor material obtained from a cancer patient. The term encompasses samples of tumor tissue, for example, tissue by radical prostatectomy and tissue obtained by biopsy, such as for example a core biopsy or a fine needle biopsy. The biological sample may be fresh, frozen, or a fixed wax embedded tissue sample, such as a paraffin embedded tissue sample, formalin fixed. A biological sample also encompasses body fluids that contain cancer cells, such as blood, plasma, serum, urine, and the like. Additionally, the term "biological sample" containing cancer cells encompasses a sample comprising tumor cells obtained from sites other than the primary tumor, for example, circulating tumor cells. The term also encompasses cells that are the progeny of the patient's tumor cells, for example cell culture samples derived from primary tumor cells or circulating tumor cells. The term further encompasses samples that may comprise protein material or nucleic acid thrown from tumor cells in vivo, for example, bone marrow, blood, serum plasma and the like. The term also encompasses samples that have been enriched for tumor cells or otherwise manipulated after their procurement and samples comprising polynucleotides and / or polypeptides that are obtained from a patient's tumor material.

The prognostic factors are those variables related to the natural history of cancer that include the recurrence rates and outcome of patients once they have developed cancer. Clinical parameters that have been associated with a worse prognosis include, for example, increased tumor stage, high PSA level in presentation, liver or high Gleason pattern. Prognostic factors are frequently used to categorize patients into subgroups with different risks of baseline recurrence.

The term prognosis is used herein to refer to the probability that a cancer patient will have a death or progression attributable to the cancer.

recurring recurrence, metastatic spread, drug resistance, of a neoplastic disease, such as prostate cancer. For example, a good prognosis would include long-term survival without recurrence and a bad prognosis would include cancer recurrence.

A positive clinical outcome can be evaluated using any endpoint that indicates a benefit to the patient, including, without limitation, (1) inhibition, some degree, of tumor growth, including deceleration and complete growth arrest; (2) reduction in the number of tumor cells; (3) reduction in tumor size; (4) inhibition (ie reduction, deceleration, or complete detection) of infiltration of tumor cells in adjacent organs and / or peripheral tissues; (5) inhibition of metastasis; (6) improvement of the anti-tumor immune response, possibly resulting in regression or rejection of the tumor; (7) relief, to some degree, of one or more symptoms associated with the tumor; (8) increase in survival duration after treatment; and / or (9) decreased mortality at a given time point after treatment. The positive clinical outcome can also be considered in the context of an outcome of a relative individual with a result of a population of patients who have a comparable clinical diagnosis, and can be evaluated using several endpoints such as an increase in the Interval duration. Without Recurrence (RFI), an increase in survival time (Total Survival (OS)) or specific survival time of prostate cancer (Prostate Cancer Specific Survival (PCSS)) in a population, without reclassification or increase in Tumor stage or Gleason grade between biopsy and radical prostatectomy, presence of grade 3 + 3 and organ confined disease in radical prostatectomy and the like.

The term risk classification means a grouping of subjects for the level of risk (or probability) that the subject will experience a particular negative clinical outcome. A subject can be classified into a risk group or classified into a level of risk based on the results of the present description, for example high, medium or low risk. A risk group is a group of subjects or individuals with a similar level of risk for a particular clinical outcome.

The term "long-term survival" is used herein to refer to survival for a particular period of time, for example, for at least 5 years, or for at least 10 years.

The term recurrence is used herein to refer to local or distant recurrence (i.e., metastasis) of cancer. For example, prostate cancer can recur locally in the tissue next to the prostate or seminal vesicles. Cancer can also affect the surrounding lymph nodes in the pelvis or lymph nodes outside this area. Prostate cancer can also spread to tissues next to the prostate, such as pelvic muscles, bones, or other organs. Recurrence can be determined by clinical recurrence detected by, for example, imaging study or biopsy, or biochemical recurrence detected by, for example, levels of sustained-monitoring prostate specific antigen (PSA) 0.4 ng / mL or onset of rescue therapy as a result of an increase in the level of

PSA

The term intervals without clinical recurrence (cRFI) is used here at the time of surgery at the first clinical recurrence or death due to the clinical recurrence of prostate cancer. If the follow-up ends without the occurrence of clinical recurrence, or other primary cancers or death, it was presented before the clinical recurrence, in time the cRFI is considered censored; When this occurs, the only known information is that through the time of censorship, clinical recurrence has not occurred in this subject. Biochemical recurrences are ignored for the purposes of calculating the cRFI.

The term interval without biochemical recurrence (bRFI) is used herein to propose the time of surgery to the first biochemical recurrence of prostate cancer. If the clinical recurrence occurred before the biochemical recurrence, the follow-up ended without the occurrence of bRFI, or other primary cancers or death occurred before the biochemical recurrence, the time to biochemical recurrence is considered censored in the first of these.

The term General Survival (OS) was used herein to refer to the time of surgery to the death of any cause. If the subject was still alive at a time of the last follow-up, the survival time is considered censored at the time of the last follow-up. Biochemical recurrence and clinical recurrence are ignored for the purposes of calculating OS.

The term Prostate Cancer Specific Survival (PCSS) is used herein to describe the time of surgery to the death of prostate cancer. If the patient did not die of prostate cancer before termination of the follow-up, or died due to other causes, the PCSS is considered censored at this time. Clinical recurrence and biochemical recurrence are ignored for the purposes of calculating PCSS.

In practice, the calculation of the time-to-event measurements listed in the above may vary from study to study depending on the definition of the events that are considered censored.

As used herein, the term "Expression Level" as applied to a gene refers to the normalized level of a gene product, for example the normalized value determined for the level of RNA of a gene or for the level of polypeptide of a gene

The term "gene product or expression product" is used herein to refer to the RNA transcription products (transcripts) of the gene, including mRNA, and the polypeptide translation products of such RNA transcripts. A gene product can be, for example, an unlicensed mRNA, an mRNA, a splice variant mRNA, a micro-RNA, a fragmented RNA, a polypeptide, a post-translationally modified polypeptide, a splice variant polypeptide, etc. .

The term "RNA transcript," as used herein, refers to the RNA transcription products of a gene, including, for example, mRNA, a spliced ​​mRNA, a splice variant mRNA, a micro-RNA and an RNA. fragmented.

Unless otherwise indicated, each gene name used herein corresponds to the Official Symbol assigned to the gene and provided by Entrez Gene (URL: www.nebí.nlm.nih.gov / sites / entrez) from the Date of submission of this application.

The term "micro array" refers to an ordered array of hybridizable array elements, for example, oligonucleotide or polynucleotide probes, in a substrate.

The term "polynucleotide" generally refers to any polyiribonucleotide or polydeoxyribonucleotide, which may be RNA or unmodified DNA or modified RNA or DNA. Thus, for example, polynucleotides as defined herein include, without limitation, single-stranded and double-stranded DNA, DNA that includes single-stranded and double-stranded regions, single-stranded and double-stranded RNA, and RNA that it includes single-stranded and double-stranded regions, hybrid molecules comprising DNA and RNA that can be single-stranded or, more typically, double-stranded or include single-stranded and double-stranded regions. In addition, the term "polynucleotide" as used herein refers to triple stranded regions comprising RNA or DNA or both RNA and DNA. The strands in such regions may be of the same molecule or of different molecules. Regions may include all or one or more of the molecules, but typically involve only a region of some of the molecules. One of the molecules of a triple helical region is often an oligonucleotide. The term polynucleotide includes cDNAs. The term includes DNAs (including cDNAs) and RNAs that contain one or more modified bases. Thus, DNAs or RNAs with modified main chains for stability or for other reasons, are polynucleotides since that term is proposed herein. On the other hand, DNAs or RNAs comprising unusual bases, such as inosine, or modified bases, such as tritiated bases, are included within the term polynucleotides as defined herein. In general, the term polynucleotides encompasses all chemically, enzymatically and / or metabolically modified forms of unmodified polynucleotides, as well as the chemical forms of DNA and RNA characteristic of viruses and cells, include simple and complex cells.

The term "oligonucleotide" refers to a relatively short polynucleotide, including, without limitation, single stranded deoxyribonucleotides, single stranded or double stranded ribonucleotides, rDNA hybrids and double stranded DNAs. Oligonucleotides, such as single-stranded DNA probe oligonucleotides, are frequently synthesized by chemical methods, for example using automated oligonucleotide synthesizers that are commercially available. However, oligonucleotides can be made by a variety of other methods, including recombinant DNA mediated techniques in vitro and by the expression of DNAs in cells and organisms.

The term Ct as used herein refers to the threshold cycle, the cycle number in the quantitative polymerase chain reaction (qPCR) in which the fluorescence generated within a reaction well exceeds the defined threshold, is say the point during the reaction at which the sufficient number of amplicons have accumulated to meet the defined threshold.

The term Cp as used herein refers to a crossing point. The Cp value is calculated by determining the second derivatives of the full qPCR amplification curves and their maximum value. The Cp value represents the cycle in which the increase in fluorescence is highest and where the logarithmic phase of a

PCR begins.

The terms threshold or threshold formation refer to a procedure used to account for the non-linear relationships between measurements of gene expression and clinical response as well as to further reduce the variation in reported patient records. When threshold formation is applied, all measurements below or above a threshold are adjusted for that threshold value. A non-linear relationship between gene expression and the result can be examined using smoother or cubic tabs to model gene expression at intervals without recurrence using Cox PH regression or an adverse disease state that uses logistic regression. D. Cox, Journal of the Royal Statistical Society, Series B 34: 187-220 (1972). Variation in reported patient records could be examined as a function of variability in gene expression at the limit of quantification and / or detection for a particular gene.

As used herein, the term "amplicon" refers to pieces of DNA that have been synthesized using techniques and amplification, such as polymerase chain reactions (PCR) and ligase chain reactions.

Astringency of hybridization reactions is easily determined by a person of ordinary experience in the field, and is generally an empirical calculation dependent on the length of the probe, washing temperature and salt concentration. In general, longer probes require higher temperatures for proper annealing, while shorter probes require lower temperatures. Hybridization generally depends on the ability of denatured DNA to anneal when complementary strands are present in an environment below their melting temperature. The higher the degree of homology desired between the probe and the hybridizable sequence, the higher the relative temperature that can be used is higher. As a result, it turns out that higher relative temperatures would tend to make the reaction conditions more severe, while lower temperatures would do less. For additional details and explanation of the astringency of hybridization reactions, see Ausubel et al., Current Protocole in Molecular Biology (Wiley Interscience Publishers, 1995).

Conditions of severity or conditions of high severity, as defined herein, typically: (1) employ low ionic strength and high temperature for washing, for example sodium chloride 0.015 M / sodium citrate 0.0015 M /0.1% of dodecil sodium sulfate at 50 ° C; (2) employ a denaturing agent during hybridization, such as formamide, for example, 50% formamide (v / v) with 0.1% bovine serum albumin / 0.1% Ficol / 0.1% polyvinylpyrrolidone / sulfate buffer solution 50mM sodium at pH 6.5 with 750mM sodium chloride, 75mM sodium citrate at 42 ° C; or (3) employ 50% formamide, 5 x SSC (0.75 M NaCl, 0.075 M sodium citrate), 50 mM sodium phosphate (pH 6.8), 0.1% sodium pyrophosphate, 5 x Denhardt's solution, DNA of salmon sperm passed through sound waves (50 pg / ml), 0.1% SDS, and 10% dextran sulfate at 42 ° C, with washes at 42 ° C in 0.2 x SSC (sodium chloride / citrate sodium) and 50% formamide, followed by a high astringency wash consisting of 0.1 x SSC containing EDTA at

55 ° C

Moderately severe conditions can be identified as described by Sambrook et al.,

Molecular Cloning: A Laboratory Manual, New York: Coid Spring Harbor Press, 1989, and include the use of wash solution and hybridization conditions (e.g. temperature, ionic strength and% SDS) less astringent than those described above. . An example of moderately severe conditions is overnight incubation at 37 ° C in a solution comprising: 20% formamide, 5 x SSC (150 mM NaCl, 15 mM trisodium citrate), 50 mM sodium phosphate (pH 7.S), 5 x Denhardt's solution, 10% dextran sulfate, and 20 mg / ml denatured cut salmon sperm DNA, followed by washing the filters in 1 x SSC at approximately 37-500C. The skilled artisan will recognize how to adjust the temperature, ionic strength, etc., as necessary to adapt factors such as probe length and the like.

The terms RNA splicing are used interchangeably and refer to RNA processing that remove introns and exon junctions to produce mature RNA with continuous coding sequence that move in the cytoplasm of a eukaryotic cell. As used herein, the term TMPRSS fusion and TMPRSS2 fusion are used interchangeably and refer to a fusion of the androgen-driven TMPRSS2 gene with the ERG oncogene, which has been shown to have a significant association with prostate cancer. S. Perner, and collaborators,

<img file="MX366164B_D0003.tif" />

Urologe A. 46 (7): 754-760 (2007); SA Narod, et al., Br J Cancer 99 (6): 847-851 (2008). As used herein, the TMPRSS positive fusion state indicates that the TMPRSS fusion is present in a tissue sample, while the negative TMPRSS fusion state indicates that the TMPRSS fusion is not present in a tissue sample. Experts in the field will recognize that there are numerous ways to determine the TMPRSS fusion state, such as quantitative, real-time PCR or high performance sequencing. See for example, K. Mertz, et al., Neoplasis 9 (3): 200-206 (2007); C. Maher, Nature 458 (7234): 97101 (2009).

The terms correlated and associated are used interchangeably herein to refer to the association between two measurements (or measured entities). The description provides genes or subsets of genes, the levels of expression of which are associated with the clinical outcome. For example, the increased expression level of a gene can be positively correlated (positively associated) with a good or positive clinical outcome. Such a positive correlation can be shown statistically in several ways, for example by a risk of cancer recurrence risk less than a ratio of probabilities of cancer augmentation or reclassification of less than one. In another example, the increased expression level of a gene can be negatively correlated (negatively associated) with a good or positive clinical outcome. In this case, for example, the patient may experience a cancer recurrence or cancer improvement / recurrence, and this can be shown statistically in several ways, for example, a hazard ratio greater than one or a likelihood ratio greater than one. . Correlation is also used herein to refer to the resistance of the association between the expression levels of two different genes, such that the expression level of a first gene can be substituted with an expression level of a second gene in an algorithm given if their expression levels correlate greatly. Such a correlated expression of two genes that are substitutable in an algorithm are usually the levels of gene expression that positively correlate with each other, for example, if the increased expression of a first gene is positively correlated with a result (for example, increased probability of a good clinical outcome), then the second gene that co-expresses and shows the expression correlated with the first gene also positively correlates with the same result.

The terms co-expressed and co-expressed, as used herein, refers to a statistical correlation between the amounts of different sequences of transcripts across a population of different patients. Co-expression in pairs can be calculated by several methods known in the art, for example, when calculating Pearson's correlation coefficients or Spearman's correlation coefficients. Select groups of co-expressed genes can also be identified by sowing and stacking the maximum select group enumeration (MCE) described in Example 4 herein. A co-expression analysis can be calculated using standardized expression data. Genes within the same subset of genes are also considered to be co-expressed.

A computer-based system refers to a system of hardware, software, and data storage media used to analyze information. The minimum hardware of a patient's computer-based system comprises a central processing unit (CPU), and hardware for data entry, data outputs (eg, display), and data storage. An ordinarily skilled artisan can easily appreciate that any of the currently available computer-based systems and / or components thereof are suitable for use in relation to the methods of the present description. The data storage medium may comprise any manufacturing comprising a

<img file="MX366164B_D0004.tif" />

recording of this information as described above, or a memory access device that can access such manufacturing.

To record the data, programming or other information in the computer-readable medium refers to a process for storing information, using any such method known in the art. Any convenient data storage structure can be chosen, based on the means used to access the stored information. A variety of data processing programs and formats can be used to store, for example word processing text file, database format, etc.

A processor or computing medium refers to any combination of hardware and / or software that will perform the functions required by it. For example, a suitable processor may be a programmable digital microprocessor such as available in the form of an electronic controller, main structure, server or personal computer {desktop or laptop). Where the processor is programmable, the appropriate programming can be communicated from a remote location to the processor, or previously stored in a computer program product (such as a portable or fixed computer readable storage medium, either an optical state device or solid, magnetic or based). For example, a magnetic medium or optical disk can carry the programming, and can be read by a suitable reader that communicates with each processor in its corresponding station.

Algorithm-Based Methods and Gene Subsets

The present invention provides an algorithm-based molecular diagnostic assay to predict a clinical outcome for a patient with prostate cancer. The level of expression of one or more genes can be used alone or arranged in subsets of functional genes to calculate a quantitative record that can be used to predict the likelihood of a clinical outcome. The algorithm-based assay and associated information provided by the practice of the methods of the present invention facilitate decision-making of optimal treatment in prostate cancer. For example, such a clinical tool would allow physicians to identify patients who have a low probability of having aggressive cancer and therefore would not need RP; or those who have a high probability of having cancer

As quantitatively be described mathematically or aggressively and therefore would need RP.

an arithmetic record or use in it is a present, numerical value calculated to help simplify or inform the analysis of the most complex quantitative information, such as the correlation of certain levels of gene expression or subsets of genes described to a probability of a clinical outcome of a patient with prostate cancer. A quantitative record can be determined by the application of a specific algorithm. The algorithm used to calculate the quantitative record in the methods described herein can group the values ​​of the level of gene expression. Gene clustering can be carried out at least in part based on knowledge of the relative contribution of genes according to physiological functions or component cell characteristics, such as in the groups raised herein. A quantitative record can be determined for a gene group (gene group record). The formation of the groups can also facilitate the mathematical weighting of the contribution of various levels of gene expression or subsets of genes to quantitative registration. The weighting of a gene or groups of genes that represents a physiological process or component cell characteristic may reflect the contribution of this process or characteristic to the pathology of the cancer and the clinical outcome, such as recurrence or increase / reclassification of the cancer. The present invention provides a number of algorithms for calculating quantitative records, for example, as set forth in Table 4. In one embodiment of the invention, an increase in the quantitative record indicates an increased probability of a negative clinical outcome.

In one embodiment, a quantitative record is a recurrence record, which indicates the likelihood of a cancer recurrence, increase or reclassification of a cancer, adverse pathology, non-organ confined disease, high-grade disease and / or high-grade disease or confined not to organ. An increase in the recurrence record can be correlated with an increase in the probability of cancer recurrence, increase or reclassification of a cancer, adverse pathology, non-organ confined disease, high-grade disease and / or high-grade or non-confined disease to organs

The gene subsets of the present invention include an ECM gene group, migration gene group, androgen gene group, proliferation gene groups, epithelial gene group, and stress gene group.

The subsets of genes referred to herein as the ECM gene group, stromal gene group, and stromal response gene group are used interchangeably and include genes that are predominantly synthesized by stromal cells and are involved in the stromal response and genes which are co-expressed, the genes of the ECM gene group. Stromal cells are referred to in • the present as connective tissue cells that constitute the supporting structure of biological tissues. Stromal cells include fibroblasts, immune cells, pericytes, endothelial cells, and inflammatory cells. Stromal response refers to a desmoplastic response of host tissues at the site of a primary tumor or invasion. See, for example, E. Rubín, J. Farber, Pathlogy, 985-986 (Ed. Final 1994). The ECM gene group includes, for example, ASPN, SFRP4, BGN, THBS2, INHBA, COL1A1, COL3A1, COL1A2, SPARC, COL8A1, COL4A1, FN1, FAP, and COL5A2, and the co-expressed genes thereof. Exemplary co-expressed genes include the genes and / or selected groups of genes shown in Table 8.

The subsets of genes referred to herein as the migration gene group or migration regulation gene group or cytoskeletal gene group or cell organization gene group are used interchangeably and include co-expressed genes and genes that are part of a network of dynamic microfilaments of actin and accessory proteins that provide intracellular support to cells, generate physical forces for cell movement and cell division, as well as facilitate intracellular transport of vesicles and cell organelles. The migration gene group includes, for example, BIN1, IGF1, C7, GSN, DES, TGFB1I1, TPM2, VCL,

<img file="MX366164B_D0005.tif" />

FLNC, ITGA7, COL6A1, PPP1R12A, GSTM1, GSTM2, PAGE4, ​​ΡΡΑΡ2Β, SRD5A2, PRKCA, IGFBP6, GPM6B, OLFML3, and HLF, and co-expressed genes thereof. Exemplary co-expressed genes and / or select groups of genes are provided in Table 9.

The subset of genes referred to herein as the androgen gene group, PSA gene group, and PSA regulation gene group are used interchangeably and include genes that are members of the calicrein family of serine proteases ( for example calicrein 3 [PSA]), and the genes that are co-expressed with the genes of the androgen gene group. The androgen gene group includes, for example, FAM13C and KLK2, and co-expressed genes thereof. The androgen gene group may also comprise AZGP1 and SRD5A2, and the co-expressed genes thereof.

The subsets of genes referred to herein as the proliferation gene group and cell cycle gene group are used interchangeably and include genes that are involved with cell cycle functions and genes that are co-expressed with the group's genes. of proliferation genes. Cell cycle functions as used herein refers to cell proliferation and cell cycle control, for example, checkpoint / phase transition from G1 to S. The proliferation gene group thus includes, for example, CDC20,

ΤΡΧ2, UBE2T, MYBL2 and CDKN2C, and the co-expressed genes thereof. Exemplary co-expressed genes and / or selected groups of genes are provided in Table 10.

The subsets of genes referred to herein as the epithelial gene group and basal epithelial gene group are used interchangeably and include genes that are expressed during differentiation of a polarized epithelium and that provide intracellular structural integrity to facilitate physical interactions with the neighboring epithelial cells, and genes that co-express with the genes of the epithelial gene groups. The epithelial gene group includes, for example, CYP3A5, KRT15, ​​KRT5, LAMB3 and SDC1 and the co-expressed genes thereof.

The subset of genes referred to herein as the stress gene group, stress response gene group, and early response gene group are used interchangeably, and includes coexpressed genes and genes that are transcription factors and proteins. of ligation to DNA activated quickly and transiently in response to cellular tension and other extracellular signals. These factors, in turn, regulate the transcription of a diverse range of genes. The group of stress genes includes, for example, DUSP1, EGR1, FOS, JUN, EGR3, GADD45B and ZFP36, and co-expressed genes thereof.

<img file="MX366164B_D0006.tif" />

Exemplary co-expressed genes and / or select groups of genes are provided in Table 11.

Expression levels of other genes and their co-expressed genes can be used with one more of the subsets of previous genes to predict a probability of a clinical outcome of a patient with prostate cancer. For example, the expression level of one or more genes selected from 81 genes of Figure 1 or Table 1A or IB that are not within any of the described gene subsets can be used with one or more of the gene subsets described. In one embodiment of the invention, one or more of STAT5B, NFAT5, AZGP1, ANPEP, IGFBP2, SLC22A3, ERG, AR, SRD5A2, GSTM1, and GSTM2 can be used in one or more subsets of genes described above to predict The probability of a clinical outcome.

The present invention also provides methods for determining a threshold expression level for a particular gene. A threshold expression level can be calculated for a specific gene. A threshold expression level for a gene can be based on a normalized expression level. In one example, a threshold expression level Cp can be calculated by evaluating functional forms using logistic regression or proportional hazard regression.

Cox

The present invention further provides methods for determining genes that co-express with the particular genes identified by, for example, quantitative RT-PCR (qRT-PCR), as validated biomarkers relevant to a particular type of cancer. Coexpressed genes are useful biomarkers. Co-expressed genes can be substituted for the genes with which they are coexpressed. Methods may include identifying the selected group of genes from the microarray data, normalizing the microarray data, calculating a Spearman correlation matrix in pairs for the array probes, filtering the significant co-expressed probes through different studies, constructing a graph, map the probe to the genes, and generate a report of selected groups of genes. An exemplary method for identifying the co-expressed genes is described in Example 3 below, and the co-expressed genes identified using this method are provided in Tables 8-11. Expression levels of one or more genes from a select group of genes can be used to calculate the probability that a patient with prostate cancer will experience a positive clinical outcome, such as a reduced reduced probability of a cancer recurrence.

Any of one or more combinations of gene groups can be tested in the method of the present invention. For example, a group of response genes

<img file="MX366164B_D0007.tif" />

Stromal can be tested, alone or in combination, with a group of cellular organization genes, a proliferation gene group, and / or an androgen gene group. In addition, any variety of genes within each gene group can be tested.

In a specific embodiment of the invention, a method of predicting a clinical outcome for a patient with prostate cancer comprises measuring an expression level of at least one gene from a group of stromal response genes, or a co-expressed gene of the same, and at least one gene from a group of genes of cellular organization, or a co-expressed gene thereof. In another embodiment, the level of expression of at least two genes from a group of stromal response genes, or a co-expressed gene thereof, and at least two genes from a group of cellular organization genes, or a gene Co-expressed thereof, they are measured. In yet another embodiment, the expression levels of at least three genes are measured from each of the stromal response gene group and the cell organization gene group. In a further embodiment, the expression levels of at least four genes are measured from each of the stromal response gene group and the cell organization gene group. In another embodiment, the expression levels of at least five genes are measured from each of the stromal response gene groups and the cell organization gene group. In still an additional embodiment, the expression levels of at least six genes are measured from each of the stromal response gene group and the cell organization gene group.

In another specific modality, the expression level of at least one gene in the stromal response gene group, or a co-expressed gene thereof, can be measured, in addition to the expression level of at least one gene in a group. of androgen genes, or a co-expressed gene thereof. In a particular embodiment, the expression levels of at least three genes, or co-expressed genes thereof, of the stromal response gene group, and the expression level of at least one gene, or co-expressed gene thereof, from the group of androgen genes can be measured.

In a further embodiment, the level of expression of at least one gene from each of the stromal response gene group, the androgen gene group, and the cell organization gene group, or co-expressed genes thereof , can be measured. In a particular embodiment, the level of at least three genes in the stromal response gene group, at least one gene in the androgen gene group, and at least three genes in the cell organization gene group can be measured. In another embodiment, the expression level of at least one gene each of the stromal response gene group, the androgen gene group, and the proliferation gene group, or the co-expressed genes thereof, can be to size. In a particular embodiment, the level of at least three genes in the stromal response gene group, at least one gene in the androgen gene group, and at least one gene in the proliferation gene group can be measured. In any of these combinations, at least two genes in the androgen gene group can also be measured. In any of the combinations, at least four genes of the androgen gene group can also be measured.

In another embodiment, the level of expression of at least one gene from each of the stromal response gene group, the androgen gene group, the cell organization gene group, and the proliferation gene group, or genes co-expressed thereof, can be measured. In a particular embodiment, the level of at least three genes from the stromal response gene group, at least three genes from the cell organization gene group, at least one gene from the proliferation gene group, and at least Two genes from the group of androgen genes can be measured. In any of the modalities, at least four genes of the androgen gene group can be measured.

Additionally, the expression levels of one or more genes that are not within the gene subsets described herein can be measured with any combination of the gene subsets described herein. Alternatively, any gene that is within a subset of genes can be analyzed separately from the subset of genes, or in another subset of genes. For example, the expression levels of at least one, at least two, at least three, or at least 4 genes can be measured, in addition to the subsets of genes described herein. In one embodiment of the invention, the additional gene (s) is selected from STAT5B, NFAT5, AZGP1, ANPEP, IGFBP2, SLC22A3, ERG, AR, SRD5A2, GSTM1, and GSTM2.

In a specific embodiment, the method of the invention comprises measuring the levels of expression of the specific combinations of genes and subsets of genes shown in Table 4. In a further embodiment, a gene group record (s) and The quantitative record (s) are calculated according to the algorithm (s) shown in Table 4.

Several technological procedures for the determination of the levels of expression of the described genes are set forth in this specification, including, without limitation, RT-PCR, microarrays, high performance sequencing, serial analysis of gene expression (SAGE). in English) and Digital Gene Expression (DGE), which will be raised in detail later. In particular aspects, the level of expression of each gene can be determined in relation to various characteristics of exon expression products that include genes, introns, protein epitopes and protein activity.

The expression product that is tested can be, for example, RNA or a polypeptide. The expression product can be fragmented. For example, the assay can use primers that are complementary to the target sequences of an expression product and thus could measure the total transcripts as well as those fragmented expression products that contain the target sequence. Additional information is provided in Table A.

The RNA expression product can be tested directly or by detection of a cDNA product that results from a PCR-based amplification method, for example, quantitative reverse transcription polymerase chain reaction (1RT-PCR). (See for example, US Patent No. 7,587,279). The polypeptide expression product can be tested using immunohistochemistry (IHC) by proteomic techniques. In addition, both RNA and polypeptide expression products can also be tested using microarrays.

Methods for Testing the Expression Levels of a

Gen product

Gene expression profiling methods include

<img file="MX366164B_D0008.tif" />

methods based on polynucleotide hybridization analysis, methods based on polynucleotide sequencing, and proteomic based methods. Exemplary methods known in the art for quantification of RNA expression in a sample include Northern staining and in si tu hybridization (Parker &amp; Barnes, Methods in Molecular Biology 106: 247-283 (1999)); RNAse protection assays (Hod, Biotechniques 13: 852-854 (1992)); and PCR-based methods, such as reverse transcription PCR (RT-PCR) (Weis and Collaborators, Trends in Genetics 8: 263-264 (1992)). Antibodies that can recognize sequence-specific duplexes, including DNA duplexes, RNA duplexes, and hybrid RNARNA duplexes or DNA protein duplexes can be employed. Representative methods for gene expression analysis based on sequencing include Serial Analysis of Gene Expression (SAGE), and gene expression analysis by massively parallel signature sequencing (MPSS). Other methods known in the art can be used.

Reverse Transcription PCR (RT-PCR)

Typically, mRNA is isolated from a test sample. The starting material is typically total RNA isolated from a human tumor, usually in a primary tumor. Optionally, normal tissues of the same patient can be used as an internal control. Such normal tissue that presents histologically adjacent to a tumor. The mRNA can be extracted from a tissue sample, for example, from a sample that is fresh, frozen (eg fresh frozen), or embedded and fixed in paraffin (for example fixed in formalin).

General methods for mRNA extraction are well known in the field and are described in standard molecular biology textbooks, including Ausubel et al., Current Protocols of Molecular Biology, John

Wiley and Sons (1997). Methods for the extraction of RNA from tissues embedded in paraphma are described, for example, in Rupp and Locker, Lab Invest. 56: A67 (1987), and De Andrés et al., BioTechniques 18: 42044 (1995). In particular, RNA isolation can be carried out using a purification kit, a set of buffer solutions and protease from commercial manufacturers, such as Qiagen, according to the manufacturer's instructions. For example, him

Total RNA from the cells in the culture can be isolated using the Qiagen RNeasy mini-columns. Other commercially available RNA isolation kits include the MR MasterPure complete DNA and RNA purification equipment (EPICENTRE®, Madison, WI), and the Paraffin Block RNA isolation (Ambion, Inc.). Total RNA from total tissue samples can be isolated using Stat-60 RNA (Tel25

Test). The tumor-prepared RNA can be isolated, for example, by gradient centrifugation of cesium chloride density.

The sample containing the RNA is then subjected to reverse transcription to produce the cDNA of the RNA template, followed by exponential amplification in a PCR reaction. The two most commonly used reverse transcriptases are the reverse transcriptase of avil myeloblastosis virus (AMV-RT) and the reverse transcriptase of Moloney murine leukemia virus (MMLV-RT). The reverse transcription step is typically prepared using specific primers, random hexamers or oligo-dT primers, depending on the circumstances and the purpose of expression profiling. For example, the extracted RNA can be cross-transcribed using a GeneAmp PCR RNA kit (Perkin Elmer, CA, USA), following the manufacturer's instructions. The derived cDNA can then be used as a template in the subsequent PCR reaction.

PCR-based methods use a thermostable DNA-dependent DNA polymerase, such as a Taq DNA polymerase. For example, TaqMan® PCR typically uses the 5'-nuclease activity of Taq or Tth polymerase to hydrolyse a hybridization probe linked to its target amplicon, but any enzyme with equivalent 5 'nuclease activity can be used. Two oligonucleotide primers are used to generate a typical amplicon for a PCR reaction product. A third oligonucleotide, or probe, can be distinguished to facilitate the detection of a nucleotide sequence of the amplicon located between the hybridization sites in the two PCR primers. The probe can be detectably labeled, for example, with a reporter dye, and can be additionally provided with both a fluorescent dye and a fast-cooling fluorescent dye, as in a TaqMan® probe configuration. Where a TaqMan® probe is used, during the amplification reaction, the Taq DNA polymerase enzyme cleaves the probe in a template-dependent manner. The resulting probe fragments dissociate in solution, and the signal from the released reporter dye is free from the rapid cooling effect of the second fluorophore. One molecule of the reporter dye is released for each new synthesized molecule, and detection of the uncooled reporter dye quickly provides the basis for quantitative interpretation of the data.

The TaqMan® RT-PCR can be carried out using commercially available equipment, such as, for example, high performance platforms, such as ABI PRISM 7700 Sequence Detection System® (Perkin-Elmer-Applied Biosystems, Foster City, CA, USA), or Light Cycler (Roche Molecular biochemicals, Mannheim, Germany). In a preferred embodiment, the procedure is executed in a LightCycler® 480 real-time PCT system (Roche Diagnostics), which is a cycling platform based on microtiter plates.

The 5'-nuclease assay data is commonly expressed initially as a threshold cycle (C_t). Fluorescence values ​​are recorded during each cycle and represent the amount of the product amplified at that point in the amplification reaction. The threshold cycle (C_t) is generally described as the point when the fluorescent signal is first recorded as statistically significant. Alternatively, the data can be expressed as a crossing point (Cp). The Cp value is calculated by determining the second derivatives of the full qPCR amplification curves and their maximum value. The Cp value represents the cycle in which the increase in fluorescence is highest and where the logarithmic phase of a

PCR begins.

To minimize errors and the effect of variation from sample to sample, RT-PCR is usually carried out using an internal standard. The ideal internal standard gene (also referred to as the reference gene) is expressed at a very constant level between cancerous and non-cancerous tissue of the same origin (i.e., a level that is not significantly different between normal and cancerous tissues), and it is not significantly affected by the experimental treatment (that is, it does not show a significant difference in the level of expression in the relevant tissue, as a result of chemotherapy exposure), and it is expressed on a very constant level between the same tissue taken from different patients. For example, reference genes useful in the methods described herein should not show significantly different levels of expression in the cancerous prostate as compared to normal prostate tissue. Exemplary reference genes used for normalization comprise one or more of the following genes: AAMP, ARF1, ATP5E, CLTC, GPS1, and PGK1. Measurements of gene expression can be normalized relative to the medium of one or more reference genes (for example, 2, 3, 4, 5, or more). Normalized expression measurements by reference may vary from 2 to 15, where a unit increase generally reflects a 2-fold increase in the amount of RNA.

Real-time PCR is compatible with both the quantitative competitive PCR, where an internal competitor for each target sequence is used for normalization, and with the quantitative comparative PCR that uses a normalization gene contained within the sample, or a maintenance gene for RT-PCR. For additional details, see, for example, Held et al., Genoma Research 6: 986-994 (1996).

The steps of a representative protocol for use in the methods of the present disclosure use paraffin embedded tissues, fixed as the source of RNA. For example, mRNA isolation, purification, primer extension and amplification can be carried out according to methods available in the art. (See, for example, Godfrey et al., J. Molec. Diagnostics 2: 84-91 (2000); Specht et al., Am. J. Pathol 158: 419-29 (2001)). Briefly, a representative process begins with the cutting of approximately 10 pm thick sections of tumor tissue samples embedded in paraffin. The RNA is then extracted, and the protein and DNA depleted from the sample containing RNA. After analysis of the RNA concentration, the RNA is transcribed in a reverse manner using the gene-specific primers followed by the RT-PCR to provide cDNA amplification products.

Intron-based PCR Primer and Probe Design

PCR primers and probes can be designed based on the sequence of exons or introns present in the mRNA transcript of the gene of interest. The primer / probe design can be carried out using publicly available software, such as the DNA BLAT software developed by Kent, WJ, Genome Res. 12 (4): 656-64 (2002), or by the BLAST software including its variations

Where necessary or desired, repetitive sequences of the target sequence can be masked to mitigate non-specific signals. Exemplary tools to achieve this include the Repeat Masker program available online through the Baylor College of Medicine, which classifies DNA sequences against a library of repetitive elements and returns to a request sequence in which the repetitive elements are masked. The masked intron sequences can then be used to design the primer sequences and probes they use for any of the publicly available primer / probe design packages, such as Primer Express (Applied Biosystems); MGB assay-by-design (Applied Biosystems); Primer3 (Steve Rozen and Helen J. Skaletsky (2000) Primer3 on the WWW by general users and for biologist programmers. See S. Rrawetz, S. Misener, Bioinformatics Methods and Protocols: Methodos in Molecular Biology, pages

365-386 (Human Press).

Other factors that may include in a PCR primer design include primer length, melting temperature (Tm), and G / C content, specificity, complementary primer sequences, and 3 'end sequence. In general, the optimal PCR primers are generally 17-30 bases in length, and contain about 20-80%, such as, for example, about 50-60% of G + C bases, and show Tm's between 50 and 80 ° C, for example from about 50 to 70 ° C.

For additional guidelines for the PCR primer and probe design see, for example Dieffenbach, CW. and collaborators, General Concepts for PCR Primer Design in: PCR Primer, A Laboratory Manual, Coid Spring Harbor Laboratory Press ,. New York, 1995, pp. 133-155; Innis and Gelfand, Optimization of PCRs in: PCR Protocols, A Guide to Methods and Applications, CRC Press, London, 1994, pp. 5-11; and Plasterer, TN Primerselect: Primer and probe design. Methods Mol. Biol 70: 520-527 (1997), the complete descriptions of which are expressly incorporated herein by reference.

Table A provides additional information regarding the sequences of primers, probes and amplicons associated with the examples described herein.

MassARRAY system¹®

In MassARRAY-based methods, such as the exemplary method developed by Sequenom, Inc. (San Diego, CA) after RNA isolation and reverse transcription, the cDNA obtained is enriched with a synthetic DNA molecule (competitor), which matches the region of target cDNA in all positions, except on an individual basis, and serves as an internal standard. The cDNA / competitor mixture is amplified by PCR and an alkaline shrimp phosphatase enzyme (SAP) treatment is post phosphorylated phosphorylation, resulting in remaining nucleotides. After inactivation of the alkaline phosphatase, the competitor's PCR and cDNA products are subjected to primer extension, which generates different mass signals for the competitor and cDNA derived PCR products. After purification these products are dispensed in a chip array, which is preloaded into components necessary for analysis with the matrix-assisted laser desorption ionization flight time spectrometry analysis (MALDI-TOF MS). The cDNA present in the reaction is then quantified by analyzing the relationships in the peak areas in the generated mass spectrum. For additional details see, for example, Ding and Cantor, Proc. Nati Acad. Sci. USA 100: 3059-3064 (2003).

Other PCR Based Methods

Additional based techniques that may find use in the methods described herein include, for example, BeadArray® terminology (Illumina, San Diego, CA; Oliphant et al., Discovery of Markers for Disease (Supplement to Biotechniques), June 2002; Ferguson and collaborators, Analytical Chemistry 72: 5618 (2000));

BeadsArray for Detection of Gene Expréssion ^ (BADGE), which uses the LuminexlOO LabMAP system^MR commercially available and multi-color coded microspheres (Luminex Corp., Austin, TX) in a rapid assay for gene expression (Yang et al., Genome Res. 11: 18881898 (2001)); and high profile expression profile analysis (Fukumura et al. Nucí. Acids. Res. 31 (16) e94 (2003).

Microarray

Expression levels of a gene or microarray of interest can also be evaluated using the microarray technique. In this method, the sequences of and

polynucleotides of; including

Oligonucleotide cDNAs) are arranged by a substrate. The arranged sequences are then contacted under conditions suitable for specific hybridization with the detectably labeled cDNA generated from RNA from a test sample. As in the RT-PCR method, the source of RNA is typically total RNA isolated from a tumor sample, and optionally from normal tissue of the same patient as an internal control or cell line. RNA can be extracted, for example, from frozen or embedded and fixed paraffin fixed tissue samples (for example fixed in formalin).

For example, the PCR-amplified inserts of the cDNA clones of a gene under test are expanded on a substrate in a dense arrangement. Usually, at least 10,000 nucleotide sequences are applied to the substrate. For example, microarranged genes, mobilized on the microchip in 10,000 elements each, are suitable for hybridization under severe conditions. Fluorescently labeled cDNA probes can be generated through the incorporation of fluorescent nucleotides by reverse transcription of RNA extracted from tissues of interest. The labeled cDNA probes applied to the chip hybridize with specificity to each DNA point in the array. After washing under severe conditions to remove non-specifically bound probes, the chip is scanned with confocal laser microscopy or by another detection method, such as a CCD camera. The quantification of the hybridization of each arranged element allows the evaluation of the corresponding RNA abundance.

With double color fluorescence, the separately labeled cDNA probes generated from two RNA sources hybridize in pairs to the array. The relative abundance of transcripts from the two sources corresponding to each specified gene is determined in this way simultaneously. The miniaturized scale of hybridization allows a convenient and rapid evaluation of the expression pattern for large numbers of genes. Such methods have shown that they have the sensitivity required to detect rare transcripts, which are expressed in some copies per cell, and to reproducibly detect at least approximately two-fold differences in expression levels (Schena et at, Proc. Nati. Acad. ScL USA 93 (2): 106-149 (1996)). Microarray analysis can be carried out by commercially available equipment, following the manufacturer's protocols, such as when using Affymetrix GenChip technology^MR, or Incyte microarray technology.

Series Analysis of Gene Expression (SAGE)

Serial gene expression analysis (SAGE) is a method that allows simultaneous quantitative analysis of a large number of gene transcripts, without the need to provide an individual hybridization probe for each transcript. First, a short sequence tag (approximately 10-14 bp) is generated that contains enough information to uniquely identify a transcript, provided that the tag is obtained from a unique position within each transcript. Then, many transcripts are linked together to form long series molecules, which can be sequenced, revealing the identity of the multiple tags simultaneously. The expression pattern of any population of the transcript can be quantitatively assessed by determining the abundance of the individual tags, and by identifying the gene that corresponds to each tag. For more detail see, for example, Velculescu et al., Science 270: 484-487 (1995); and Velculescu et al., Cell 88: 243-51 (1997). Analysis of Gene Expression by Acid Sequencing

Nucleic

Nucleic acid sequencing technologies are suitable methods for the analysis of gene expression. The principle underlying these methods is that the number of times a cDNA sequence is detected in a sample is directly related to the relative expression of the RNA corresponding to that sequence. These methods are sometimes referred to by the term Digital Gene Expression (DGE) to reflect the discrete numerical property of the resulting data. The early methods that apply this principle were Series Analysis of Gene Expression (SAGE) and harmful parallel signature sequencing (MPSS). See, for example, S. Brenner, et al., Nature Biotechnology 18 (6): 630-634 (2000). More recently, the advent of next-generation sequencing technologies has made the DGE simpler, higher throughput, and more affordable. As a result, more laboratories are able to use DGE to classify the expression of more genes in more individual patient samples than previously possible. See, for example, J. Marioni, Genome Research 18 (9): 1509-1517 (2008); R. Morin, Genome Research

18 (4): 610-621 (2008); A. Mortazavi, Nature Methods 5 (7): 621628 (2008); N. Cloonan, Nature Methods 5 (7): 613-619 (2008).

RNA Isolation of Body Fluids

Methods for isolating RNA for blood, plasma and serum expression analysis have been described (see, for example, K. Enders, et al., Clin Chem 48,1647-53 (2002) (and references cited herein. ) and urine (see, for example, R. Boom, et al., J Clin Microbiol. 28, 495-503 (1990) and references cited herein).

Tochemical Immunohis

Immunohistochemical methods are also suitable for detecting gene expression levels and are applied to the method described herein. Antibodies (eg, monoclonal antibodies) that specifically bind a gene product of a gene of interest can be used in such methods. The antibodies can be detected by direct labeling of the antibodies themselves, for example, with radioactive tags, fluorescent tags, aftene tags such as, biotin, or enzyme such as horseradish peroxidase or alkaline phosphatase. Alternatively, the unlabeled primary antibody can be used in conjunction with a specific labeled secondary antibody for the primary antibody. Immunohistochemistry protocols and kits are well known in the field and are commercially available.

Proteotoxic

The term proteome is defined as the totality of the proteins present in a sample (for example tissue, organism, or cellular tissue) at a certain point of time. Proteomics includes, among other things, the study of global changes in protein expression in a sample (also referred to as expression proteomics). Proteomics includes the following steps: (1) separation of individual proteins in a sample by 2-D gel electrophoresis (2-D PAGE); (2) identification of the individual proteins recovered from the gel, for example by mass spectrometry or N-terminal sequencing, and (3) analysis of the data using bioinformatics.

General Description of mRNA Isolation, Purification and Amplification

The steps of a representative protocol for profiling gene expression using fixed paraffin embedded tissues, such as the source of RNA, including RNA isolation, purification, primer extension and amplification are provided in several published journal articles. (See, for example, TE Godfrey, et al., J. Molec. Diagnostics 2: 84-91 (2000); K. Specht et al., Am. J. Pathol. 158: 419-29 (2001), M. Cronin, et al., Am J Pathol 164: 35-42 (2004)). Briefly, a representative process begins with the cutting of a tissue sample section (for example approximately 10 pm thick section of a tumor tissue sample embedded in paraffin). The RNA is then extracted, and the protein and DNA are removed. After analysis of the RNA concentration, the repair of the RNA is carried out if desired. The sample is then subjected to analysis, for example by reverse transcription using gene specific promoters followed by RT-PCR.

Statistical Analysis of Expression Levels in the

Gene Identification

A person skilled in the field will recognize that there are many statistical methods that can be used to determine if there is a significant relationship between a clinical outcome of interest (eg, recurrence) and expression levels of a marker gene as described herein. In an exemplary embodiment, the present invention includes three studies. The first study is a stratified cohort sampling design (a form of case-control sampling) that uses tissues and data from patients with prostate cancer. Sample selection was stratified by clinical T stage (TI, T2), year of surgery (&lt;1993, ^ 1993), and Gleason prostactectomy record (low / intermediate, high). All patients with clinical recurrence were selected and a certified random sample of patients who did not experience a clinical recurrence was selected. For each patient, up to two enriched tumor samples and a tissue sample that appears normal were tested. The second study used a subset of 70 patients from the first study whose matching prostate biopsy tumor tissue was tested. The third study included all patients (170 evaluable patients) who had had surgery for their prostate cancer between 1999 and 2010 at the Cleveland Clinic (CC) and had low or intermediate risk (by AUA) of clinically localized prostate cancer who could have been a reasonable candidate for active surveillance but those who underwent RP in CC within 6 months of the diagnosis of prostate cancer by biopsy. The tumor tissue biopsy of these patients was tested.

All hypothesis tests were reported using the two-sided p-values. To investigate whether there is a significant relationship of outcomes (e.g., intervals without clinical recurrence (cRFI), interval without biochemical recurrence (bRFI), prostate cancer specific survival (PCSS), general survival (OS)) with individual genes, and demographic or clinical covariates), Cox proportional hazard models (PH) using maximum weighted partial pseudo-probability estimators were used and the p-values ​​of the Wald tests of the null hypothesis that the hazard ratio (HR) is one are reported. To investigate whether there is a significant relationship between the individual genes and the Gleason pattern of a particular sample, ordinal logistic regression models are used using the maximum weighted pseudoprobability methods and the p-values ​​of the Wald tests of the null hypothesis are reported. that the relationship of possibilities (OR) is one. To investigate whether there is a significant relationship between individual genes and the increase and / or reclassification or adverse pathology in RP, logistic regression models using maximum weighted pseudoprobability methods were used and p-values ​​of the Wald tests of the null hypothesis are reported. that the relation of possibilities (OR) is one.

Coexpression Analysis

In an exemplary modality, the correlation of union of gene expression levels between prostate cancer samples under study can be evaluated. For this purpose, correlation structures between genes and samples can be examined through hierarchical clustering methods. This information can be used to confirm that genes that are known to be highly correlated in prostate cancer samples are grouped together as expected. Only genes that show a nominally significant relationship (unadjusted p &lt;0.05) with cRFI in the non-varied Cox PH regression analysis are included in these analyzes.

An expert in the field will recognize that many

<img file="MX366164B_D0009.tif" />

Co-expression analysis methods now known or subsequently developed will be within the scope and spirit of the present invention. These methods can incorporate, for example, correlation coefficients, co-expression network analysis, select group analysis, etc., and can be based on RT-PCR expression data, microarrays, sequencing, and other similar technologies. For example, gene expression clusters can be identified using pairwise analysis of the correlation based on Pearson's correlation coefficients or

Spearman (See, for example, Pearson K. and Lee A., Biometrika 2, 357 (1902); C. Spearman, Amer. J. Psychol 15: 72-101 (1904); J. Myers, A. Well, Research Design and Statistical Analysis, p. 508 (2nd Ed., 2003)). An exemplary method for identifying co-expressed genes is described in Example 3 below.

Normalization of Expression Levels

Expression data used in the methods described herein can be normalized. Normalization refers to a process to correct (normalize), for example, the differences in the amount of RNA tested and the variability in the quality of the RNA used, to remove unwanted sources of enzymatic variation in Ct measurements or Cp, and the like. With respect to RT-PCR experiments involving archived fixed paraffin embedded tissue samples, systematic sources of variation are known to include the degree of RNA degradation relative to the age of the patient sample and the type of fixative used to store the sample. Other sources of systematic variation are attributable to laboratory processing conditions.

Assays can provide normalization by incorporating the expression of certain normalization genes, which do not differ significantly in expression levels under the relevant conditions. Exemplary normalization genes described herein include maintenance genes. (See, for example, E. Eisenberg, et al., Trends in Genetics 19 (7): 362-365 (2003)). Normalization can be based on the medium or medium signal (Ct or Cp) of all genes tested or a large subset thereof (global standardization procedure). In general, normalization genes, also referred to as reference genes, are typically genes that are known to not show significantly different expression in prostate cancer as compared to non-cancerous prostate tissue, and are tracked with various conditions. Sample and process, thus provide normalization of foreign effects.

In exemplary modalities, one or more of the following genes are used as references whereby mRNA expression data is normalized: AAMP, ARF1, ATP5E, CLTC, GPS1, and PGK1. C measurements_T o Weighted average Cp calibrated for each of the prognostic and predictive genes can be normalized relative to the average of five or more reference genes.

Those experts in the field will recognize that standardization can be achieved in numerous ways, and the techniques described above are only intended to be exemplary, not exhaustive.

Standardization of Expression Levels

Expression data used in the methods

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variation a wider range of expression (a wider range of expression) than others. Standardization is carried out by dividing each expression value by its standard deviation across all samples for this gene. Danger relationships are then interpreted as the proportional change in the danger to the clinical endpoint (clinical recurrence, biological recurrence, dies due to prostate cancer, or death due to any cause) due to an increase in standard deviation 1 in the expression .

Invention Kits

The materials for use in the methods of the present invention are suitable for the preparation of kits produced in accordance with well known procedures. The present description thus provides kits comprising comprising agents, which may include probes and / or gene specific or gene selective primers, to quantify the expression of the described genes to predict the outcome or prognostic response to treatment. Such kits may optionally contain reagents for RNA extraction from tumor samples, in particular fixed paraffin embedded tissue samples, and / or reagents for RNA amplification. In addition, the kits may optionally comprise the reagent (s) with a description or identification tag or instructions in relation to their use in the methods of the present invention. The kits may comprise containers (including microtiter plates suitable for use in an automated implementation of the methods), each with one or more of the various materials or reagents (typically in concentrated form) used in the methods, including, for example , chromatographic columns, prefabricated microarrays, buffer solutions, appropriate nucleotide triphosphates (eg, dATP, dCTP, dGTP and dTTP; or rATP, rCTP, rGTP and UTP), reverse transcriptase, DNA polymerase, RNA polymerase, and one or more probes and primers of the present invention (e.g., appropriate poly (T) or random length primers linked to a reactive promoter with RNA polymerase). The mathematical algorithms used to estimate or quantify predictive forecasting information are also appropriately potential components of kits.

Reports

The methods of this invention, when practiced for commercial diagnostic purposes, generally produce a report or brief description of the information obtained from the methods described herein. For example, a report may include information regarding the expression levels of one or more genes, tumor classification or the risk of patient occurrence, probably classification of patient prognosis or risk, clinical and pathological factors, and / or other information. The methods and reports of this invention may further include storing the report in a database. The method can

0 create a record in a database for the subject and populate the record with data. The report can be a paper report, an audit report, or an electronic record. The report can be displayed and / or stored on a computing device (for example, portable device, desktop computer, portable device, desktop computer, smart device, web site, etc.). It is contemplated that the report be provided to a doctor and / or the patient. The reception of the report may also include establishing a network connection to a server computer that includes the data and reports and requests the data and reports it from the server computer.

Computer program

The values ​​of the assays described in the foregoing, such as expression data, can be calculated and stored manually. Alternatively, the steps described in the foregoing can be carried out completely or partially by a computer program product. The present invention further provides a computer program product that includes a computer readable storage medium that has a computer program stored therein. The program can, when read by a computer, perform relevant calculations based on the values ​​obtained from the analysis of one or more biological samples of an individual (for example, levels of gene expression, normalization, standardization, threshold formation, and conversion of the values ​​of the trials to a record and / or to a text or graphic representation of the tumor stage information and related). The computer program product has stored in it a computer program has a computer program stored in it to carry out the calculation.

The present description provides systems for executing the program described above, the system that generally includes: a) a central computing environment; b) an input device, operatively connected to the computing environment, to receive patient data, wherein the patient data may include, for example, level of expression or other value obtained from an assay using a biological sample of the patient, or microarray data, as described in detail in the foregoing; c) an output device, connected to the computing environment, to provide information to a user (eg, medical personnel); and d) an algorithm executed by the central computing environment (for example, a processor), where the algorithm is executed based on the data received by the input device, and where the algorithm calculates an expression register, threshold formation, other functions described herein. The methods provided by the present invention can also be automated in whole or in part.

Having described the invention, it will be more readily understood by reference to the following examples, which are provided by way of illustration, and are not intended to limit the invention in any way.

Examples

EXAMPLE 1: SELECTION OF 81 GENES FOR THE DEVELOPMENT OF

ALGORITHM

A gene identification study to identify genes associated with clinical recurrence, biochemical recurrence and / or death of prostate cancer is described in US Provisional Applications Nos. 61 / 368,217, filed on July 27, 2010; 61 / 414,310, filed on November 16, 2010; and 61 / 485,536, filed on May 12, 2011, and U.S. Publication No. 20120028264, filed on July 2, 5, 2011, and published on February 2, 2012 (all of which is incorporated herein by reference). The RT-PCR analysis was used to determine the levels of RNA expression for 732 genes and the reference genes in prostate cancer tissue and surrounding normal-looking tissue (NAT) in patients with treated early stage prostate cancer with radical prostatectomy. Significantly associated genes (p &lt;0.05) with intervals without clinical recurrence (cRFI), intervals without biochemical recurrence (bRFI), prostate cancer specific survival (PCSS), and augmentation / reclassification were determined.

Of the genes that were identified as being associated with the outcome, 81 genes were selected for the development of subsequent algorithms. The primers, probes, and sequences

<img file="MX366164B_D0010.tif" />

of amplicons of the 81 genes (and the 5 reference genes) are listed in Table A. The genes selected were among the most prognostic with respect to cRFI and other properties and were shown in Tables 1A-1B. Other properties considered were: 1) More potent genes with respect to the regression to the mean corrected standardized hazard ratio for the association of gene expression and cRFI in the tumor in the primary Gleason pattern; 2) consistency in the association (danger relationship) with the cRFI using the highest Gleason pattern tumor; 3) Associated with prostate cancer specific survival (PCSS); 4) Powerful hazard relationship after adjustment for The University of San Francisco Cancer of the Prostate Risk Assessment (CAPRA) (Cooperberg et al., J. Urol. 173: 1983-1942, 2005); 5) Relationship of statistically significant possibilities for the association between gene expression and the surgical Gleason pattern of the tumor; 6) Large total variability with greater variability among patients than the variability within the preferable patient; and 7) Highly expressed.

The degree of actual discovery rate of the association method (TDRDA) (Crager, Stat Med. 2010 Jan 15, -29 (1): 33-45.) Was used in the analysis of gene expression and the cRFI results were shown in Table 1A. The actual discovery rate is the counterpart to the false discovery rate. Non-varied Cox PH regression models were adapted and the TDRDA method was used to correct the estimated standardized hazard ratios for mean regression (RM) and evaluate false discovery rates for the identification of genes with a ratio of absolute standardized hazard of at least a specified level.

False discovery rates were controlled at 10%. The TDRDA method identifies the sets of genes among which a specified proportion is expected to have an absolute association (at this point, the absolute standardized hazard ratio) of a specified degree or more. This leads to a method of gene classification that uses the lowest bound maximum degree (MLB) of association for which each gene belongs to a set of TDRDA. Estimates of each degree of current association of the gene with approximate correction for selection bias due to regression to the medium can be derived using simple bivariate normal theory and empirical Bayes procedure of Efron and Tibshirani. Efron, Annals of Applied Statistics 2: 197-223 (2008); Efron and Tibshirani. Genetic Epidemiology 23: 70-86. Table 1A shows the RM-corrected estimate of the standardized hazard ratio and MLB for each gene that uses either the gene expression of primary Gleason pattern (PGP) or higher Gleason pattern (HGP) samples. Genes marked with an association direction of -1 are associated with a reduced probability of clinical recurrence, while those marked with an association direction of 1 are associated with an increased probability of clinical recurrence.

Variance components within the patient and between patients were estimated using a mixed model that treats the patient's effect as random. The mean and standard deviation of the normalized gene expression as well as the components within and between the patient of the variance are shown in Table 1A.

Non-varied Cox PH regression models that use the estimation of maximum weighted partial pseudoprobability were used to estimate the association between gene expression and prostate cancer specific survival (PCSS). The standardized hazard ratio (HR), the value p and the value q that use the Storey FDR method is reported in Table IB. Storey, Journal of the Royal Statistical Society, Series B 64: 479-498 (2002). The value q can be interpreted as the subsequent probability of empirical Bayes given to the data that the identified gene is a false discovery, that is, the probability that has no association with clinical recurrence.

Non-varied ordinal logistic regression models were used to estimate the association between gene expression and the Gleason pattern of the primary Gleason pattern tumor (3, 4, 5). The ratio of standardized probabilities (OR), value p and value q using the Storey FDR method is reported in Table IB.

Figure 1 shows an example of a dendrogram representing the association of the 81 genes. The y axis corresponds to the average distance between the groups measured as 1-Pearson r. The smaller the number (distance measure), the more highly the genes correlate. The amalgamation method is the average of the weighted peer group. The genes that were co-expressed were identified from the dendrogram and grouped into the gene groups. Based on Figure 1, the genes of the gene identification study were formed in the following groups or subsets of genes:

Group of cellular organization genes (ΒΓΝ1; IGF1; C7; GSN; DES; TGFB1I1; TPM2; VCL; FINC; ITGA7; COL6A1; PPP1R12A; GS1M1; GS1M2; PAGE4; PPAP2B; SRD5A2; PRKCA; IGFBP6; GFM3B; GFM3B; )

Group of basal epithelial genes (CYP3A5; KRT15; KRT5; LAMB3;

SDC1)

Group of stress response genes (DUSP1; EGR1; POS; JUN; EGR3; GADD45B; ZFP36)

Androgen gene group (FAM13C; KLK2; AZGP1; SRD5A2)

Stromal gene group (ASEN; SFRP4; BGN; THBS2; INHBA; COL1A1; C0L3A1; C0L1A2; SPARC; COL8A1; COL4A1; FN1; FAP; COL5A2)

Proliferation gene group (CDC20; TPX2; UBE2T; MYBL2; CDKN2C) c

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<td rowspan="3">8 6 4 s i</td><td colspan="2"> §</td><td>I 1.1297541 |</td><td>I 1.0554846 |</td><td> | 1.4007391 |</td><td>SW H</td><td> | 1.1229959 |</td><td> | 1.2116705 |</td><td> | 1.4829005 |</td><td>Γ 1,327,1052 |</td><td> | 1.3485096 |</td><td> | 1.3086551 |</td><td>tn SW 1 * 1 or g H</td><td> | 1.4304656 |</td><td> | 1.4007391 |</td><td> 1 1.3702593 |</td><td> | 1.2287532 |</td><td> | 1.2801791 |</td><td> | 1.3310925 |</td><td> | 1.220182 |</td><td>I 1,2649088 |</td><td>I 1.2840254 |</td><td> | 1.1525766 |</td><td> | 1.2226248 |</td><td> | 1.4520843 |</td><td> | 1.2361479 |</td><td> | 1.4304656 |</td><td>I 1.2398619 |</td><td> | 1.4035433 |</td><td> | 1.004008 |</td><td>£ 8 P.S</td><td>I 1.3525612 |</td><td> | 1.3008267 |</td><td> | 1.3337573 |</td><td>i to P.S</td><td> | 1.2687092 |</td><td> | 1.0639623 |</td>

<td colspan="2">0 gg</td><td> 1.3719705 |</td><td>H 3 3 H</td><td>you £ ?! r ^ H</td><td> 1.4080433 |</td><td>you § or SW ro i — 1</td><td> | 1.4709656 |</td><td>s 5 CO 00 H</td><td>one 3 us H</td><td>I 1.6210275 |</td><td> | 1.5553089 |</td><td> 1 1.2186754 |</td><td> | 1.8669598 |</td><td>SW tn 8 co P i — 1</td><td> 1 1.6810573 |</td><td>SW tn two 8 tn</td><td> | 1.5773643 |</td><td>co i — 1 8 SW p ^</td><td>8 § «Φ pH</td><td> 1.5652799</td><td>you 6 00 tn P.S</td><td>co § i-1</td><td> | 1.4927024 ¡</td><td> | 1.7981441 |</td><td> | 1.4966995 ¡</td><td>8 S CO</td><td>I 1.4723607 |</td><td> | 1.7787926 |</td><td>s 3 to P.S</td><td> | 1.7140049 |</td><td> | 1.6372299 |</td><td>r- AND § P.S</td><td>rd γ- γο SW i — 1</td><td>it is 9 (OR rd</td><td>! 3 P.S US</td><td> | 1.2436215 |</td>

<td colspan="2"> 8</td><td>H</td><td>P.S</td><td>H l</td><td>H l</td><td>H one</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td> «—1 1</td><td>H one</td><td>P.S</td><td>pH I</td><td>p4 one</td><td>i — 1</td><td>H one</td><td>i — 1 one</td><td>p4 i</td><td>Rh</td><td>pH</td><td>pH</td><td>p4</td><td>p-1</td><td>p-1 one</td><td>P.S one</td><td>P.S</td><td>P.S</td><td>rd</td><td>P.S i</td><td>P.S</td><td>H one</td><td>rd one</td><td>P.S one</td>

<td rowspan="3">8 • 8 Λ 8 8</td><td colspan="2"> §</td><td>d one H r-1</td><td>I £ H rd</td><td>§ SW £ H</td><td>3 d H</td><td>tn you § H d H</td><td>s d il</td><td>3 H</td><td>one H</td><td>H</td><td>g g&gt; 8 d H</td><td>3 d laughed</td><td>tn £ SW d &lt;· H</td><td>3 3 d rd</td><td>§ 3 M pH</td><td>to SW you you p4 p4</td><td>§ 3 d pH</td><td>£ OR c * $ d pt</td><td>g 8 pH</td><td>00 s you 3 d pH</td><td>p4 3 to rt</td><td>co i pH</td><td>to you δ 1 ^</td><td>s &lt;Ώ F it is pH</td><td>I 1.1936311!</td><td>co 8 3 d pl</td><td>d ro 1—1</td><td>P rt</td><td></td><td>CO 3 d P.S</td><td>YOU rd SW g to rd</td><td>g one ro rd</td><td>g to rd</td><td>§ 8 « rl</td><td>one 9 d rd</td><td>OR 8 P.S</td>

<td colspan="2"> 0</td><td>t- 3 s » 1-1</td><td>3 (D you 3 H</td><td>CO to SW ?! CO H</td><td>8 S S H</td><td>YOU 8 H.H r- H</td><td>to 8 P tn H</td><td>3 H</td><td>two 9 H</td><td>Lg 3 H</td><td>H</td><td>tn 00 It is H</td><td>£ to tn CO</td><td>YOU g rd</td><td>H</td><td>i ι-H</td><td>Γ * p.m one pH</td><td>to i to i — l</td><td>P ^</td><td>5! to Rh</td><td>one to tn p.m</td><td>8 3 to 1 * 1 pH</td><td>d SW tn p.m</td><td>8 3 SW i-1</td><td>3 p.m</td><td>d Ώ i — l</td><td>SW pl</td><td>i — 1 s SW 3 pl</td><td>ω £ i — 1</td><td>§ P.S</td><td>g 3 i — 1</td><td>R 8 S SW P.S</td><td>CO 8 i P.S</td><td>P.S</td><td>YOU CD r-</td><td>8 US 3 to P.S</td>

<td colspan="2">or í 1 í</td><td>H one</td><td>H one</td><td>H one</td><td>H</td><td>H one</td><td>H one</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H one</td><td>p4</td><td>i — I «</td><td>p4 one</td><td>p &lt;</td><td>r4</td><td>i — 1 one</td><td>i — 1 one</td><td>pH one</td><td>i-1 one</td><td>pH</td><td>p-1 one</td><td>Rh one</td><td>pH</td><td>rd one</td><td>rd</td><td>P.S</td><td>rd</td><td>P.S</td><td>P.S</td><td>rd</td><td>w</td><td>rd</td>

<td></td><td colspan="2">Variance total</td><td>in US Γ- CO us m d or</td><td>HIS Yes 8 3 OR</td><td>Γ- Η S ?! SW H</td><td>SW to £ It is or</td><td>§ to SW or</td><td>d 8 SW s or</td><td>YOU i h H</td><td>03 3 SW tn 3 OR</td><td>to H</td><td>r- YOU CO YOU d 8 ©</td><td>r- £ in H d tn or</td><td>d SW 3 Γ- CD r- H</td><td>H 8 co 8 ro ro</td><td>s CM pH r- m &lt;* s oj</td><td>You P § co rd</td><td>YOU to you £ pH rt</td><td>tn you d § d H</td><td>r SW SW § pl</td><td>s § 8 P.S</td><td>8 H s d Rh</td><td>00 co SW d</td><td>H H CO P pl</td><td>&lt;n pH SW OR YOU SW co or</td><td>to § or</td><td>you Γ- γο ro § pH</td><td>OO 8 d to d</td><td>d 3 YOU tn</td><td>It is Γ- £ 8 OR</td><td>P 3 to rd</td><td>CO or 3 OR P.S ro d</td><td>tn d P.S</td><td>rd US SW SW US CD you or</td><td>g or</td><td>m P SW • Φ or</td><td>m 00 Γ- Η H Γζ OR</td>

<td></td><td colspan="2">3 i</td><td>to to H OR</td><td>you r — 1 ro ΓΟ OR</td><td>3 ρ or</td><td>s H d</td><td>£ d or</td><td>co d you fO or</td><td>§ SW or</td><td>co r- 3 or</td><td>H YOU (OR fO OR</td><td>you 8 us or</td><td>YOU co d ro or</td><td>§ d «—I</td><td>to you i — l</td><td>m s pH</td><td>? pH</td><td>3 «*) it is or</td><td>SW s m d</td><td>tn to d</td><td>or</td><td>£ * * or</td><td>tn d or</td><td>00 P tn or</td><td>H you co d or</td><td>SW r- to or</td><td>YOU £ SW OR</td><td>m s tn or</td><td>8 ΓΟ SW P.S</td><td>3 £ OR d</td><td>3 SW d</td><td>you 3 d</td><td>you 3 ro OR</td><td>SW to sp or</td><td>co c ro d</td><td>tn s. or</td><td>00 3 or</td>

<td></td><td colspan="2">hi</td><td>^ d SW to</td><td>8 d d</td><td>SW P CO or</td><td>r- 8 d or</td><td>to ro or</td><td>3 'í or</td><td>3 * or</td><td>or</td><td> §</td><td>g ©</td><td>8 H OR</td><td>SW tn or</td><td>you 3 ro p-1</td><td>(OR co m co OR</td><td>3 8 OR</td><td>£ OR</td><td>you to &lt;s or</td><td>53 you co</td><td>you s 00 or</td><td>tn 8 CO or</td><td>you 3</td><td>g d i — 1</td><td>00 tn d</td><td>r- 8 m d</td><td>or</td><td>£ tn SW pl</td><td>tn SW co</td><td>you s d</td><td>YOU 3 or</td><td>two or</td><td>two co d</td><td>8 US d</td><td>00 8 d or</td><td>3 d or</td><td>G d or</td>

<td></td><td>j 6 i</td><td></td><td>in one or</td><td>you δ Yes r- or</td><td>to you H you SW d t — 1</td><td> £ 8</td><td>3 SW CO Γ- or</td><td>i § co or</td><td>i H</td><td>Γ- r- ©</td><td>d 3 00 in 00 SW or</td><td> £</td><td>ro g 9 or</td><td>two tn SW fO ro H</td><td>3 it is H</td><td></td><td>§ to s n rl</td><td>to 3 g p4</td><td>pH 3 to 1— |</td><td>tn ! d pH</td><td>3 SW §</td><td>tn i — l i — l</td><td> | 0.8297195</td><td>pH s SW n &lt;* t p-1</td><td>p-1 8 OR</td><td>6 SW or</td><td> | 1.0515294</td><td>SW 8 pl</td><td>SW to ro 9 ro d</td><td>to co s m or</td><td>Γ- 3 YOU £ P.S P.S</td><td>$ i tn US or</td><td>s S to rd</td><td>rd P you or</td><td>8 § CO</td><td>00 P.S to 3 SW d</td><td>one or</td>

<td></td><td>j 8</td><td> 1</td><td>d to you SW ro you</td><td>you you d 3 'Ί d</td><td>g CO R tn</td><td>you £ SW g ed</td><td>you one H d CO</td><td>8 H 3 to</td><td>SW d</td><td>s 8 ro</td><td>d it is you s 1 * 1</td><td>8 r- ro</td><td> | 3.5015369 |</td><td>d $ 8 tn</td><td>You 3 8 CO</td><td>two d</td><td>CO 8! SW &lt;* s SW</td><td>i — 1 co tn Yes CJ pH</td><td>YOU SW s f * l to</td><td>YOU § r * (B ed</td><td>you 3 two to</td><td>3 s d rd</td><td>g you Hey to</td><td>Rh w K · i heard</td><td> | 7.4923611 ¡</td><td>3 F! to</td><td>you 8 SW § tn</td><td>sa you one f * S you</td><td>00 ro s 8 P.S C *</td><td>g 3 ro d</td><td> §</td><td>8 8 R CO</td><td>US 3 s US d</td><td>d g 00 P.S d</td><td>US co SW 3 SW US</td><td>SW to d</td><td>co í§ 8 to</td>

<td></td><td colspan="2">i</td><td> 1</td><td> 1</td><td> 1</td><td>g</td><td>H H</td><td> !</td><td></td><td>or</td><td>i</td><td> 1</td><td> 8</td><td> !</td><td>i</td><td>i</td><td> 1</td><td> 1</td><td> §</td><td>i</td><td> §</td><td></td><td>i</td><td>s</td><td></td><td> §</td><td></td><td>i</td><td>I</td><td>g</td><td>i</td><td> §</td><td>i</td><td></td><td> §</td><td>Y</td><td>i</td>

tn tn rd

ΙΑ table

<td rowspan="2"> § •8</td><td colspan="2"> §</td><td> 1.2788996</td><td> 1.2032184</td><td></td><td>in r * rl OR co I heard H</td><td> 1.2287532</td><td> 1.4035433</td><td> 1.217744</td><td> 1.1320159</td><td> 1.3112751</td><td>I 1.2995265 1</td><td></td><td> 1.2448313</td><td> 1.3271052 1</td><td>m in 04 co 8 rl Rh</td><td>\ £ f s 3 in rl</td><td>1.1817543 j</td>

<td>l</td><td></td><td>8 to Ώ</td><td>i — 1 § s sj</td><td>or* a Ώ 00 04 OR</td><td>8 P1 β in</td><td>CO to &lt;0 R</td><td>οι S 00 04</td><td>m m § &lt;*</td><td>THE ÍÉ in</td><td>in 8 OR or</td><td>σι £ 3 co a CD m</td><td>&lt;n co 8 g</td><td>3 m 3 •to·</td><td>Η 3 s</td><td>8 SW &lt;4&gt; θ ' 3</td><td>00 s K0 s</td><td>in R OR to</td>

<td></td><td> 1</td><td></td><td></td><td>i — 1</td><td>i — 1</td><td>H</td><td>rl</td><td>ι — 1</td><td>ι — 1</td><td>H</td><td>rl</td><td> «—1</td><td>il</td><td>H</td><td>Rh</td><td>rl</td><td></td><td>i — l</td>

<td>s</td><td colspan="2"></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td rowspan="2">ΐ §</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td colspan="2" rowspan="2">to</td><td rowspan="2">H</td><td rowspan="2">rl</td><td rowspan="2">i — 1</td><td rowspan="2">il</td><td rowspan="2">rl</td><td rowspan="2">γΗ</td><td rowspan="2"> «—1</td><td rowspan="2">i — 1</td><td rowspan="2">rl</td><td rowspan="2">rl I</td><td rowspan="2">rt</td><td rowspan="2">rl</td><td rowspan="2">«H</td><td rowspan="2">H one</td><td rowspan="2">H</td><td rowspan="2"> (—1</td>

<td></td>

<td> 8</td><td></td><td></td><td>| —1 § » in I heard</td><td>one YOU I heard</td><td>a 3 OR 8 or</td><td>Ld 5 8 m</td><td>one two? σι I heard</td><td>ιη S 01 8 σι</td><td>g » θ CO the I heard</td><td>tH 3 04</td><td>i 8 rn ι — I</td><td>in 3 in Ώ fO</td><td> 3 § 8</td><td>OI 8 3 04</td><td>£ 3 8 OJ</td><td>rl θ ' 00 in 9 OJ</td><td>s r ^</td><td>8; &lt;n OI to</td>

<td>•to</td><td>g</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>λ</td><td>l'i</td><td></td><td>&lt;0 s 00 in</td><td>to or a in £ in</td><td>or</td><td>04 P THE 04 P</td><td>&lt;í in 04 αο the m the</td><td> 3 8</td><td></td><td>in rl I heard 00 s in</td><td>3 8 THE the</td><td>iH 8 ¡N P</td><td>OR· 5 0? co</td><td>CN in tn 3 m</td><td></td><td>and&gt; to I heard in •to·</td><td>g 3</td><td>3 H 8</td>

<td>s</td><td>s</td><td></td><td>I — 1</td><td>ι — 1</td><td>Γ |</td><td>«H</td><td>rl</td><td>Η</td><td>i — I</td><td>i — 1</td><td>rl</td><td>rl</td><td>H</td><td>r-4</td><td>rl</td><td> 1—(</td><td>i — l</td><td>i — l</td>

<td> §</td><td> 88</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 1</td><td></td><td></td><td>rd</td><td>Rh</td><td>p4</td><td>H</td><td>Η</td><td>Η</td><td>iH</td><td>i — 1</td><td>rl</td><td>Rh</td><td>rd</td><td>you</td><td>iH</td><td> 1</td><td>rl</td><td>iH</td>

<td></td><td colspan="2">to «£</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> §</td><td></td><td> 3</td><td>g</td><td>s θ '</td><td></td><td>CD in 00</td><td>σι 8</td><td>θ ' OR</td><td rowspan="2">in LD ¡§ rl</td><td>rl in t</td><td>θ ' to</td><td>CO 3</td><td>ΙΛ g</td><td>I heard</td><td>to R</td><td>00 σι in</td><td>il In</td>

<td></td><td> 1 ?</td><td></td><td>m</td><td> 8 0*</td><td> 3</td><td>s</td><td> 00</td><td>ιη</td><td> 8</td><td>δ</td><td>8 tn 04</td><td></td><td> §</td><td> 1</td><td>£ OJ 04</td><td></td><td>ΙΛ vo</td>

<td></td><td> “ ⁴</td><td></td><td>rl</td><td>or</td><td>in</td><td>cH</td><td>ο</td><td>ο</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>i — 1</td><td>OR</td><td>r- (</td><td>or</td>

<td></td><td colspan="2"> 3</td><td>3 00 m</td><td>8 m</td><td>8 00 or</td><td>σ! THE THE</td><td></td><td> § 04</td><td>gj</td><td> 3 04</td><td>Φ</td><td>or- co £ CO</td><td>P</td><td>8 co</td><td>OI to Y?</td><td>in oo to</td><td>8 P</td><td>\or to m</td>

<td></td><td colspan="2">H.H hi</td><td>or</td><td>or</td><td>r-1</td><td>OR</td><td>ο</td><td>Ο</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td>

<td></td><td>to</td><td> |</td><td>to n in</td><td>00 «* L m n</td><td>θ ' P «—1</td><td>rl 3 THE</td><td> 3</td><td> 8 &lt;*&gt;</td><td>il tn 00 rl</td><td>i m</td><td> 8</td><td>0 » 3 i — 1</td><td>rt 3</td><td>\or or- to</td><td>CO to n</td><td>it is rl £</td><td>to in KO</td><td>8 in or</td>

<td></td><td>h</td><td>i</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td>or</td><td>r- |</td><td>OR</td><td></td><td></td>

<td></td><td>j</td><td></td><td>one OJ 04</td><td>00 3 s co</td><td>or? i £ I heard</td><td> 0-</td><td>m 8 &lt;0 00 ο-</td><td>ιη R 8 8</td><td>i 8 m</td><td>B OJ I heard the P</td><td>! m 8</td><td>to § tn</td><td>8 s I</td><td>in 8 φ i — l t- in</td><td>in 8 in £</td><td>ε in 0-</td><td>or- 8 or in or-</td><td>to 8 or 53</td>

<td></td><td>ft í</td><td> 8</td><td>r4</td><td></td><td>OR)</td><td></td><td>ο</td><td>Ο</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>rl</td><td>or</td>

<td></td><td></td><td></td><td>&lt;X&gt; in 3 to</td><td>I heard 3 i — 1 p co</td><td></td><td>or- 8 m 8</td><td>the σι S ιη CO</td><td>ιη Ο- g ιη</td><td>s ¡8 in</td><td>rl to LD or in in</td><td>in 8 3 in</td><td>R P</td><td>u&gt; 3 in i</td><td>it is m</td><td>in s vo VO 8</td><td>&lt;D in u&gt; r</td><td>a 3 &amp; OR</td><td>«—I 3 OR- 3 in</td>

<td></td><td>&amp; í</td><td> 1</td><td>UP</td><td>Lf)</td><td>Γ</td><td>Mr</td><td></td><td> 0-</td><td>il</td><td>co</td><td></td><td>in</td><td>θ '</td><td>θ '</td><td>co</td><td></td><td></td><td>co</td>

<td></td><td></td><td></td><td></td><td>s</td><td></td><td>IT IS or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>to</td><td></td><td></td><td></td>

<td></td><td> 8</td><td></td><td> 1</td><td>i</td><td>i</td><td></td><td>I</td><td> 1</td><td> 1</td><td>i</td><td>i</td><td> 1</td><td></td><td>Yes</td><td> 1</td><td>i</td><td> 1</td><td> 1</td>

LO r — I

<img file="MX366164B_D0013.tif" />

IB table

<td>you</td><td></td><td>Φ</td><td></td><td>H</td><td>H</td><td> 00</td><td>SW</td><td>SW</td><td>SW</td><td>SW</td><td> 00</td><td>d</td><td></td><td>SW</td><td>d</td><td>r-</td><td>SW</td><td>you</td><td>in</td><td>YOU</td><td>SW</td><td></td><td> 00</td><td>OR</td><td>SW</td>

<td> 0</td><td></td><td> *0</td><td></td><td>OR</td><td> 00</td><td>Γ0</td><td> 00</td><td>SW</td><td>or</td><td>or</td><td>in</td><td>d</td><td>d</td><td>in</td><td>rd</td><td>n</td><td>or</td><td>d</td><td></td><td>OR</td><td>YOU</td><td>SW</td><td>or</td><td></td><td>or</td>

<td>Q</td><td></td><td></td><td></td><td>in</td><td>r-</td><td>ΓΊ</td><td>H</td><td>SW</td><td> 1</td><td> 1</td><td>rd</td><td>SW</td><td>a</td><td>m</td><td>in</td><td>d</td><td> 1</td><td>SW</td><td>d</td><td> |</td><td>a</td><td>you</td><td> 1</td><td> 1</td><td>l</td>

<td> &lt;0</td><td></td><td rowspan="2">you*</td><td></td><td>r-</td><td>Γ *</td><td> 00</td><td> 00</td><td>SW</td><td>K</td><td>to</td><td>OR</td><td>Φ</td><td>in</td><td> 3*</td><td>or</td><td>or</td><td>ω</td><td>you</td><td>or</td><td>K</td><td>you</td><td>or</td><td>to</td><td>to</td><td>to</td>

<td>Φ</td><td></td><td></td><td> 00</td><td>r-</td><td></td><td>THE</td><td>Ό</td><td>in</td><td>• φ</td><td>OR</td><td>d</td><td>or</td><td>in</td><td>in</td><td>or</td><td>SW</td><td>ΈΡ</td><td>or</td><td>or</td><td></td><td>or</td><td>Γ</td><td>Ί *</td><td>d</td>

<td>i — 1</td><td></td><td></td><td></td><td> 00</td><td>in</td><td rowspan="2"></td><td> &lt;*»</td><td> 00</td><td>oo</td><td>in</td><td>or</td><td>in</td><td>or</td><td>SW</td><td>in</td><td>or</td><td>H</td><td>rd</td><td>or</td><td> 00</td><td>d</td><td>or</td><td>d</td><td>d</td><td>a</td>

<td> 0</td><td></td><td>b</td><td>Φ</td><td>in</td><td>or</td><td>rd</td><td>rn</td><td></td><td></td><td>or</td><td>d</td><td>or</td><td>d</td><td>d</td><td>or</td><td></td><td>in</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td></td><td></td>

<td></td><td></td><td>OR</td><td>b</td><td></td><td></td><td>d</td><td></td><td></td><td>d</td><td>rd</td><td></td><td></td><td></td><td></td><td></td><td></td><td>d</td><td></td><td></td><td>H</td><td></td><td></td><td> •3«</td><td>rd</td><td>d</td>

<td>Φ</td><td></td><td></td><td> 0</td><td>or</td><td>or</td><td></td><td>OR</td><td>or</td><td></td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td></td><td></td>

<td>Ό</td><td></td><td> ©</td><td>Xi</td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>you</td><td></td><td> &gt;</td><td>CQ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>h</td><td></td><td>Φ</td><td></td><td>a</td><td>sp</td><td></td><td> 00</td><td>in</td><td>r</td><td>Γ-</td><td>SW</td><td>rd</td><td> 00</td><td> ^3*</td><td>a</td><td>in</td><td>r-</td><td></td><td>SW</td><td></td><td>you</td><td></td><td>YOU</td><td>d</td><td></td>

<td>x&gt;</td><td></td><td>Ό</td><td></td><td></td><td>or</td><td></td><td>in</td><td>Φ</td><td>or</td><td>OR</td><td>or</td><td>d</td><td>rd</td><td>SW</td><td>YOU</td><td>in</td><td>or</td><td>or</td><td>or</td><td>H</td><td>SW</td><td>SW</td><td>or</td><td>H</td><td>or</td>

<td> ©</td><td></td><td></td><td></td><td> 00</td><td>SW</td><td>esi</td><td>or</td><td>SW</td><td> 1</td><td> 1</td><td> 1</td><td> &lt;3·</td><td>d</td><td>rd</td><td>or</td><td> &lt;3&lt;</td><td> 1</td><td> 00</td><td> 1</td><td> 1</td><td>in</td><td>d</td><td> 1</td><td> 1</td><td> 1</td>

<td>I heard</td><td></td><td> 0*</td><td></td><td></td><td>Γ</td><td>m</td><td>in</td><td>in</td><td>W</td><td>H</td><td>w</td><td>a</td><td>rd</td><td>in</td><td>or</td><td>OR</td><td>H</td><td>or</td><td>M</td><td>ω</td><td>SW</td><td>or</td><td>to</td><td>to</td><td>to</td>

<td></td><td></td><td></td><td></td><td>or</td><td></td><td rowspan="2">m</td><td>SW</td><td>Φ</td><td>d</td><td>you</td><td>or</td><td>rd</td><td>OR</td><td> &lt;3*</td><td>in</td><td>OR</td><td>SW</td><td>in</td><td>US</td><td>or</td><td>in</td><td>or</td><td>rd</td><td>SW</td><td>a</td>

<td> |-(</td><td></td><td></td><td></td><td>in</td><td>in</td><td>co</td><td>in</td><td>in</td><td>rd</td><td></td><td>rd</td><td>OR</td><td>rd-</td><td>d</td><td>or</td><td>or</td><td>SW</td><td>SD</td><td>US</td><td>d</td><td>or</td><td>H</td><td>d</td><td>SW</td>

<td>Φ</td><td></td><td></td><td> *0</td><td></td><td>or</td><td>yes·</td><td>rd</td><td> 00</td><td></td><td></td><td></td><td></td><td>OR</td><td>a</td><td></td><td>or</td><td></td><td>SW</td><td></td><td></td><td>or</td><td>or</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td>in</td><td>rd</td><td>d</td><td></td><td></td><td></td><td></td><td>or</td><td>d</td><td></td><td>US</td><td>SW</td><td></td><td></td><td>d</td><td>in</td><td>d</td>

<td>you 0 OR</td><td></td><td> 10 &gt;</td><td> &lt;0 2</td><td></td><td>or</td><td>or</td><td>OR</td><td>or</td><td></td><td></td><td></td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td></td><td></td><td>or</td><td>or</td><td></td><td></td><td></td>

<td>you</td><td></td><td></td><td></td><td>in</td><td>Γ</td><td>a</td><td>in</td><td>us</td><td>r-</td><td>in</td><td>d</td><td>in</td><td> &lt;3·</td><td>a</td><td>SW</td><td>rd</td><td>H</td><td>a</td><td>in</td><td>M *</td><td>US</td><td>in</td><td>H</td><td>d</td><td> &lt;3*</td>

<td>Ό</td><td></td><td></td><td></td><td>r-</td><td>or</td><td>d</td><td>a</td><td></td><td> 00</td><td>rd</td><td>M¹</td><td>in</td><td></td><td> &lt;3·</td><td>rd</td><td>a</td><td>SW</td><td>a</td><td>or</td><td>YOU</td><td></td><td>or</td><td>SW</td><td></td><td>r *</td>

<td>• H</td><td>or</td><td></td><td></td><td>d</td><td>or</td><td>in</td><td>in</td><td>in</td><td>rd</td><td>Γ-</td><td>r »</td><td>t</td><td> 00</td><td>OR</td><td> 00</td><td>SD</td><td>you</td><td>you</td><td>LfS</td><td>a</td><td>or</td><td>SW</td><td>you</td><td>a</td><td>SW</td>

<td>or</td><td>«H</td><td> »</td><td></td><td>d</td><td>SW</td><td></td><td>rd</td><td>us</td><td>oo</td><td>in</td><td> ·&lt;*</td><td>SW</td><td> *3·</td><td>in</td><td>• 'Ψ</td><td> 00</td><td>'J *</td><td>SW</td><td>r-</td><td>a</td><td>H</td><td>• sf</td><td>SW</td><td>r-</td><td>rd</td>

<td> ©</td><td>b</td><td>JJ</td><td></td><td>oo</td><td>-Φ</td><td rowspan="3">in d</td><td>Γ *</td><td>r «</td><td>r</td><td>r-</td><td>or</td><td>d</td><td>rn</td><td>you</td><td>in</td><td>rd</td><td>d</td><td>or</td><td>oo</td><td>you</td><td>in</td><td>or</td><td>'J ·</td><td> 00</td><td>in</td>

<td>• H</td><td>ifl</td><td>Q</td><td></td><td>in</td><td>a</td><td>d</td><td>r-</td><td>rd</td><td></td><td>in</td><td>d</td><td>or</td><td> 00</td><td>d</td><td>r ~</td><td>SW</td><td> &lt;3*</td><td> 3·</td><td>CO</td><td>or</td><td>r-</td><td>in</td><td>SW</td><td>«Φ</td>

<td>OR</td><td>fi</td><td rowspan="2">W</td><td></td><td></td><td>in</td><td> 00</td><td>or"</td><td>SW</td><td>m</td><td>d</td><td>rd</td><td>you</td><td>or</td><td>rd</td><td>m</td><td>in</td><td>YOU</td><td>a</td><td>SW</td><td> &lt;3·</td><td> 00</td><td> &lt;3·</td><td>in</td><td></td>

<td> 0</td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Q</td><td>b</td><td>I heard</td><td></td><td></td><td>H</td><td>r1</td><td>or</td><td>or</td><td>d</td><td>d</td><td>d</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>d</td><td>d</td><td>or</td><td>d</td><td>d</td><td>H</td><td>rd</td><td>or</td><td>or</td><td>or</td>

<td></td><td> &amp;</td><td>OR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Φ</td><td></td><td> *3«</td><td> 01</td><td></td><td>H</td><td>rn</td><td>SW</td><td>SW</td><td>r-</td><td> 00</td><td>SW</td><td>t- *</td><td> 00</td><td>a</td><td>you</td><td>in</td><td>r-</td><td>a</td><td></td><td>SW</td><td>SW</td><td>Γ</td><td>a</td>

<td></td><td></td><td> •0</td><td></td><td>a</td><td>in</td><td>i — 1</td><td> 00</td><td>Φ</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>SW</td><td>ω</td><td>in</td><td>H</td><td>SW</td><td>or</td><td>H</td><td>US</td><td> «3*</td><td>or</td><td>you</td><td>ao</td>

<td>or</td><td></td><td></td><td></td><td>SW</td><td>ao</td><td></td><td>d</td><td>in</td><td> 1</td><td> 1</td><td> 1</td><td>ao</td><td> &gt;</td><td>d</td><td>US</td><td>r *</td><td>d</td><td>or</td><td> 1</td><td>a</td><td> **</td><td>H</td><td>I</td><td>d</td><td>a</td>

<td> *0</td><td></td><td></td><td></td><td> 00</td><td>SW</td><td>OR</td><td></td><td>or</td><td>W</td><td>W</td><td>w</td><td>in</td><td>H</td><td> &lt;3·</td><td></td><td>SW</td><td></td><td>in</td><td>W</td><td>H</td><td></td><td>OR</td><td>to</td><td>rd</td><td></td>

<td> ©</td><td></td><td colspan="2">you * s.</td><td>you</td><td>r</td><td></td><td>r-</td><td>d</td><td>rd</td><td>rd</td><td>in</td><td>in</td><td>YOU</td><td>rd</td><td>SW</td><td></td><td>d</td><td>d</td><td>in</td><td>OR</td><td></td><td>OR</td><td>d</td><td>OR</td><td>or</td>

<td>X&gt;</td><td></td><td>b</td><td>Φ</td><td>d</td><td> 00</td><td></td><td>a</td><td>you</td><td>t-</td><td>r-</td><td>h-</td><td>in</td><td>d</td><td>OR</td><td> 00</td><td>OR</td><td>H</td><td>r-</td><td></td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td>

<td>Q</td><td></td><td> 0</td><td>b</td><td></td><td>or</td><td> 00</td><td>φ</td><td>or</td><td></td><td></td><td></td><td>rd</td><td></td><td>OR</td><td>rd</td><td>OR</td><td>OR</td><td>or</td><td></td><td>or</td><td>σ</td><td>c</td><td></td><td>or</td><td>or</td>

<td>you</td><td></td><td></td><td>or</td><td></td><td></td><td>d</td><td></td><td></td><td> 00</td><td> 00</td><td>in</td><td></td><td>rn</td><td></td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td> ”3·</td><td></td><td></td>

<td>ΤΊ</td><td></td><td> ©</td><td>X »</td><td>or</td><td>or</td><td> •</td><td>or</td><td>or</td><td></td><td></td><td></td><td>OR</td><td></td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td>

<td>c</td><td></td><td> &gt;</td><td>m</td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 3</td><td></td><td>Φ</td><td></td><td>SD</td><td>SW</td><td>SD</td><td>in</td><td>Φ</td><td>Γ-</td><td></td><td>in</td><td>in</td><td> 00</td><td> 00</td><td>d</td><td></td><td> 00</td><td>you</td><td>you</td><td>a</td><td>d</td><td>r-</td><td></td><td>a</td><td>a</td>

<td>0j</td><td></td><td>•you</td><td></td><td>m</td><td>oo</td><td>rd</td><td>&lt;n</td><td>ao</td><td>or</td><td>OR</td><td>or</td><td>a</td><td>or</td><td>r-</td><td>SW</td><td>a</td><td>d</td><td>φ</td><td>or</td><td>or</td><td>r-</td><td>or</td><td>OR</td><td>or</td><td>or</td>

<td></td><td></td><td></td><td></td><td>m</td><td>r-</td><td>or</td><td>rd</td><td>d</td><td> 1</td><td> 1</td><td>l</td><td>rd</td><td> 1</td><td>or</td><td>in</td><td>rd</td><td> 00</td><td></td><td> 1</td><td> 1</td><td>rn</td><td> 1</td><td>l</td><td>I</td><td> 1</td>

<td>or</td><td></td><td></td><td></td><td>in</td><td>co</td><td></td><td>OR</td><td>d</td><td>ω</td><td>H</td><td>ω</td><td>d</td><td>ω</td><td>SW</td><td>OR</td><td>rd</td><td>rd</td><td></td><td>ω</td><td>to</td><td>SW</td><td>to</td><td>to</td><td>to</td><td>to</td>

<td></td><td></td><td>Λ</td><td></td><td>a</td><td>ri</td><td> *!</td><td>d</td><td>Φ</td><td>a</td><td>YOU</td><td>SW</td><td>d</td><td>co</td><td>in</td><td>US</td><td>SW</td><td> 00</td><td>or</td><td> 00</td><td></td><td>SW</td><td></td><td>a</td><td>rn</td><td>r-</td>

<td> *</td><td></td><td></td><td></td><td>d</td><td>in</td><td></td><td>t</td><td>us</td><td>r *</td><td>d</td><td></td><td>you</td><td>d</td><td>or</td><td>SW</td><td>rd</td><td>a</td><td>or</td><td>d</td><td>co</td><td>rd</td><td>a</td><td>in</td><td></td><td>H</td>

<td>H</td><td></td><td>b</td><td></td><td>m</td><td></td><td>SD</td><td>in</td><td> 00</td><td></td><td></td><td></td><td>«Φ</td><td></td><td>or</td><td>in</td><td>OR</td><td>or</td><td>SW</td><td></td><td></td><td>Ό</td><td></td><td></td><td></td><td></td>

<td>b I heard</td><td></td><td> 0</td><td>•you</td><td>oo</td><td>or</td><td>m &lt;3</td><td>in</td><td>or</td><td>in</td><td>in</td><td>it is</td><td>rd</td><td>SW</td><td>or</td><td>d</td><td>OR</td><td>or</td><td>or</td><td> *3*</td><td>H</td><td>OR</td><td>Γ '</td><td>H</td><td>H</td><td> 00</td>

<td>OR</td><td></td><td> (0</td><td> (0</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td></td><td></td><td>OR</td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td></td>

<td>you 0</td><td></td><td> &gt;</td><td> ¡£</td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>OR</td><td></td><td></td><td></td><td>r-</td><td>d</td><td>THE</td><td>d</td><td>in</td><td></td><td>rd</td><td>r-</td><td>in</td><td> 00</td><td>rd</td><td> 00</td><td>SW</td><td>d</td><td>rd</td><td></td><td>r *</td><td></td><td>you</td><td> *·</td><td> 00</td><td>in</td>

<td>rt</td><td></td><td></td><td></td><td>SW</td><td> 00</td><td>m</td><td>a</td><td>in</td><td>OR</td><td>in</td><td>a</td><td>t</td><td> «3*</td><td> 00</td><td></td><td>or</td><td>M *</td><td>in</td><td>a</td><td>you</td><td> 00</td><td>in</td><td>you</td><td>H</td><td>d</td>

<td> '0</td><td></td><td></td><td></td><td>SW</td><td>or</td><td>or</td><td>or</td><td>in</td><td>r-</td><td>rd</td><td>rd</td><td>m</td><td> 10</td><td> *3*</td><td>you</td><td>γη</td><td>or</td><td> 00</td><td>a</td><td>rn</td><td>in</td><td>you</td><td>in</td><td>d</td><td>r-</td>

<td></td><td></td><td></td><td></td><td>r-</td><td>SW</td><td>θ</td><td>r ~</td><td>oo</td><td>or</td><td>rd</td><td>in</td><td>you</td><td>r-</td><td>co</td><td>d</td><td>SW</td><td>co</td><td>or</td><td>r-</td><td>or</td><td>in</td><td>or</td><td>US</td><td>or</td><td>H</td>

<td>or</td><td></td><td> »</td><td></td><td>or</td><td>Φ</td><td rowspan="2">iñ</td><td>or</td><td>d</td><td> 00</td><td>m</td><td> 00</td><td>in</td><td>in</td><td>d</td><td>Γ '</td><td>you</td><td>a</td><td></td><td>or</td><td>a</td><td>d</td><td> -3*</td><td>rd</td><td>SW</td><td>d</td>

<td>Φ</td><td></td><td>χ)</td><td></td><td></td><td></td><td>you</td><td>d</td><td>SW</td><td></td><td>r-</td><td>d</td><td>in</td><td>or</td><td>d</td><td>H</td><td>a</td><td> &lt;3*</td><td>SW</td><td></td><td>d</td><td>rd</td><td>d</td><td>SW</td><td>oo</td>

<td></td><td></td><td>m</td><td></td><td>in</td><td>oo</td><td></td><td></td><td>or</td><td> 00</td><td>in</td><td>in</td><td>or</td><td>d</td><td> *3·</td><td>or</td><td>d</td><td>r-</td><td>SW</td><td>oo</td><td>r *</td><td>rd</td><td>YOU</td><td>in</td><td>H</td><td>you</td>

<td>or</td><td></td><td>M</td><td></td><td>H</td><td>r-</td><td>THE</td><td>or</td><td></td><td>you</td><td>SW</td><td>* r</td><td>in</td><td>a</td><td>rd</td><td>d</td><td>SW</td><td>in</td><td></td><td>YOU</td><td>SW</td><td> 00</td><td> 00</td><td>a</td><td>SW</td><td>a</td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>m</td><td></td><td>I heard</td><td></td><td>H</td><td>d</td><td></td><td>rd</td><td>d</td><td>rd</td><td>d</td><td>d</td><td>rd</td><td>d</td><td>d</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>rd</td><td>rd</td><td>H</td><td>rd</td><td>or</td><td>or</td><td>or</td>

<td> ©</td><td></td><td>AND</td><td></td><td></td><td></td><td>rd</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Φ</td><td></td><td>in</td><td>in</td><td>SD</td><td></td><td> &lt;3·</td><td>SW</td><td></td><td>'φ</td><td>rn</td><td>r-</td><td>a</td><td>YOU</td><td>Γ *</td><td> *3«</td><td>oo</td><td> *3·</td><td></td><td>d</td><td>SW</td><td>US</td><td>oo</td><td> 00</td>

<td>v</td><td></td><td>•you</td><td></td><td>m</td><td> 00</td><td>d</td><td>rd</td><td>d</td><td>OR</td><td>* í *</td><td>d</td><td>SW</td><td>rd</td><td>SW</td><td>a</td><td>H</td><td>Φ</td><td>in</td><td>d</td><td>d</td><td>you</td><td>US</td><td>SW</td><td>r-</td><td>rd</td>

<td>rn</td><td></td><td></td><td></td><td>or</td><td> 00</td><td>m</td><td>SW</td><td>you</td><td>l</td><td>rd</td><td>rd</td><td>or</td><td>d</td><td> «3*</td><td>or</td><td></td><td>rn</td><td>H</td><td>rd</td><td>you</td><td>rd</td><td>d</td><td> &lt;3*</td><td></td><td>rd</td>

<td>or</td><td></td><td rowspan="2">ty</td><td></td><td>d</td><td>M ·</td><td rowspan="2">in</td><td>rd</td><td></td><td>W</td><td>OR</td><td>OR</td><td>in</td><td>d</td><td>SW</td><td>rd</td><td>SW</td><td> 00</td><td>Γ *</td><td>OR</td><td>a</td><td>d</td><td>or</td><td>SW</td><td>H</td><td>OR</td>

<td>b</td><td></td><td></td><td> *3·</td><td>or</td><td>SW</td><td>in</td><td>r-</td><td>OR</td><td>OR</td><td>You</td><td>OR</td><td>or</td><td>rd</td><td>H</td><td>you</td><td>SW</td><td>or</td><td>or</td><td>H</td><td>or</td><td>OR</td><td>OR</td><td>r-</td>

<td></td><td></td><td>b</td><td> ©</td><td> 00</td><td></td><td></td><td>Φ</td><td>SW</td><td>you</td><td>OR</td><td>OR</td><td>in</td><td>or</td><td>or</td><td>rd</td><td>OR</td><td>or</td><td>SW</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td></td>

<td></td><td></td><td> 0</td><td>b</td><td>us</td><td>or</td><td>THE</td><td>in</td><td>us</td><td></td><td></td><td>OR</td><td>OR</td><td>OR</td><td></td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td></td><td>OR</td><td>or</td>

<td> ©</td><td></td><td></td><td> 0</td><td></td><td></td><td>a &lt;</td><td></td><td></td><td>&gt; m</td><td>OR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>you</td><td></td><td>irt</td><td>JJ</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td></td><td>OR</td><td>or</td><td>OR</td><td></td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td></td><td>or</td><td>or</td>

<td>• H</td><td></td><td>t&gt;</td><td> 01</td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Me</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td>Φ</td><td></td><td>in</td><td>Γ</td><td>r-</td><td>d</td><td>you</td><td>ao</td><td>SW</td><td>r-</td><td>co</td><td>SW</td><td>a</td><td>YOU</td><td>r-</td><td>rd</td><td>rd</td><td>Γ *</td><td>co</td><td>d</td><td>r-</td><td>you</td><td>SW</td><td>rd</td>

<td>JJ</td><td></td><td>•you</td><td></td><td>or</td><td>H</td><td>SW</td><td>d</td><td>rd</td><td>or</td><td>OR</td><td>or</td><td>F*</td><td>or</td><td>rd</td><td>d</td><td>or</td><td> 00</td><td>in</td><td>or</td><td></td><td>a</td><td>or</td><td>SW</td><td>or</td><td>d</td>

<td>you</td><td></td><td></td><td></td><td>in</td><td> 00</td><td></td><td> &lt;3·</td><td>YOU</td><td> 1</td><td> 1</td><td>l</td><td>r-</td><td>l</td><td>d</td><td>or</td><td>H</td><td>r-</td><td>or</td><td>I</td><td>id</td><td>SW</td><td> 1</td><td>d</td><td> 1</td><td> &lt;3·</td>

<td> 3</td><td></td><td>to</td><td></td><td>d</td><td>a</td><td></td><td>or</td><td>r-</td><td>W</td><td>CO</td><td>w</td><td> 00</td><td>H</td><td> 00</td><td> 00</td><td>OR</td><td>a</td><td>d</td><td>ω</td><td>or</td><td>OR</td><td>to</td><td> 00</td><td>to</td><td>SW</td>

<td></td><td></td><td></td><td></td><td>in</td><td>rd</td><td></td><td>in</td><td>us</td><td>US</td><td></td><td>SW</td><td>or</td><td>d</td><td>OR</td><td>rd</td><td>OR</td><td>H</td><td>'T</td><td>Γ *</td><td>or</td><td>or</td><td>r *</td><td>OR</td><td>SW</td><td>XP</td>

<td></td><td></td><td>b</td><td></td><td> 00</td><td>r-1</td><td></td><td>us</td><td>or</td><td> 00</td><td>in</td><td>rd</td><td>rd</td><td>d</td><td>OR</td><td>OR</td><td>or</td><td>OR</td><td>d</td><td>or</td><td>or</td><td>or</td><td>you</td><td>or</td><td>you</td><td>rd</td>

<td></td><td></td><td>n</td><td>Ό</td><td>in</td><td>or</td><td>SD</td><td>in</td><td>in</td><td></td><td></td><td></td><td>OR</td><td></td><td>OR</td><td>or</td><td></td><td>OR</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td>or</td><td></td><td>OR</td>

<td>Φ</td><td></td><td>H</td><td>rd</td><td></td><td></td><td>CO</td><td></td><td></td><td>rd</td><td>d</td><td>rd</td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td>rd</td><td></td><td></td><td>d</td><td></td><td> ^3*</td><td></td>

<td></td><td></td><td> &lt;0</td><td> (0</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td></td><td></td><td>OR</td><td></td><td>OR</td><td>or</td><td></td><td>OR</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td>or</td><td></td><td>OR</td>

<td>you 0 p</td><td></td><td> &gt;</td><td> £</td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>you</td><td></td><td></td><td></td><td>in</td><td>SW</td><td>i^-1</td><td> 00</td><td> 00</td><td>SW</td><td>d</td><td>in</td><td>a</td><td> 00</td><td> 00</td><td></td><td>YOU</td><td>H</td><td>you</td><td>CJS</td><td>r</td><td>d</td><td>a</td><td>d</td><td>r «</td><td>a</td>

<td>Ό</td><td></td><td></td><td></td><td>&lt;n</td><td>Γ-</td><td>or</td><td>d</td><td>r-</td><td>SD</td><td></td><td></td><td></td><td>a</td><td>SW</td><td>r *</td><td>d</td><td>in</td><td>ao</td><td>in</td><td>co</td><td>in</td><td>r *</td><td>H</td><td>SW</td><td>you</td>

<td>• H</td><td></td><td></td><td></td><td>H</td><td> «-1</td><td> [*&gt;</td><td>'j ·</td><td></td><td>rd</td><td>in</td><td>d</td><td>or</td><td></td><td>in</td><td></td><td> &lt;3·</td><td>or</td><td>a</td><td>oo</td><td>or</td><td>H</td><td></td><td>in</td><td>r-</td><td>'Φ</td>

<td>or</td><td></td><td> »</td><td></td><td>SW</td><td>rd</td><td rowspan="3">SD d</td><td>in</td><td>rd</td><td>r ~</td><td>ID</td><td>or</td><td>Γ '</td><td>a</td><td>T</td><td>d</td><td>C</td><td>d</td><td>SW</td><td>SW</td><td>SW</td><td>YOU</td><td>or</td><td>d</td><td>a</td><td></td>

<td>Φ</td><td></td><td>X »</td><td></td><td>r-</td><td> 00</td><td></td><td>OR</td><td> &lt;3·</td><td>you</td><td></td><td>SW</td><td>rd</td><td>or</td><td>oo</td><td>ao</td><td>in</td><td>SW</td><td>you</td><td>rn</td><td>'í ·</td><td>SW</td><td>oo</td><td>or</td><td>rd</td>

<td>• H</td><td></td><td>to</td><td></td><td>&lt;n</td><td>oo</td><td> 00</td><td> 00</td><td>a</td><td>in</td><td></td><td>or</td><td>CD</td><td>r *</td><td>in</td><td>SW</td><td>you</td><td>in</td><td>a</td><td>ao</td><td>d</td><td>r-</td><td>US</td><td>in</td><td> 00</td>

<td>OR</td><td></td><td>ω</td><td></td><td>you</td><td>b '</td><td>OR</td><td></td><td>in</td><td>or</td><td>SW</td><td>a</td><td>SW</td><td>in</td><td>you</td><td>you</td><td>H</td><td>you</td><td>a</td><td>or</td><td>rn</td><td></td><td>a</td><td>SW</td><td>a</td><td>SW</td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>d</td><td></td><td></td><td></td><td></td>

<td>m</td><td></td><td>HR</td><td></td><td>or</td><td>Η</td><td>t — 1</td><td></td><td>or</td><td>in</td><td>d</td><td>d</td><td>rd</td><td>d</td><td>rd</td><td>rd</td><td>d</td><td>rd</td><td>H</td><td>in</td><td>d</td><td></td><td>d</td><td>or</td><td>or</td><td>or</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>d</td><td></td><td></td><td>d</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>to</td><td rowspan="2">to</td><td></td><td></td><td></td><td></td><td>d!</td><td></td><td></td><td>rf!</td><td></td><td></td><td></td><td></td><td></td><td> «3·</td><td>Γ)</td><td>d</td><td></td><td></td><td>to</td>

<td></td><td></td><td></td><td></td><td>H</td><td>a</td><td>rd</td><td>rd</td><td>Z</td><td></td><td>rd</td><td>rd</td><td>in</td><td> «3·</td><td>a</td><td></td><td></td><td></td><td>m</td><td>b</td><td></td><td>rn</td><td>H</td><td></td><td>SW</td>

<td></td><td></td><td> 2</td><td></td><td>b</td><td>b</td><td>AND-"</td><td>Saw</td><td></td><td>CU</td><td>Z</td><td>rl</td><td></td><td>OR</td><td></td><td></td><td>I heard</td><td>b</td><td>H</td><td></td><td>C</td><td></td><td>to</td><td>Z</td><td></td><td>il</td>

<td></td><td></td><td>H</td><td></td><td>I heard</td><td>Η</td><td> 1-3</td><td>you</td><td>V)</td><td>VJ</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>d</td><td></td><td> &amp;</td><td> 2</td><td>b</td><td>b</td><td> 33</td><td>H</td><td>Γ</td><td>OR</td>

<td></td><td></td><td> 0</td><td></td><td> 3</td><td>c</td><td>OR</td><td>OR</td><td>cu</td><td>* C</td><td></td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>b</td><td>b</td><td>b</td><td>H</td><td>w</td><td>ω</td><td>AND-"</td><td>CQ</td><td>or</td><td>OR</td>

what or

in m

xi «5

Η

<td>you</td><td></td><td> ©</td><td>r-</td><td> 00</td><td> 0·</td><td>to</td><td> 00</td><td>rt</td><td> 0·</td><td>rt</td><td>or-</td><td> 00</td><td>Γ *</td><td>to</td><td> 00</td><td> 01</td><td>θ '</td><td> 01</td><td>in</td><td>Γ</td><td>co</td><td>co</td><td>in</td><td>in</td><td>&lt;P</td><td> ©·</td>

<td> 0</td><td></td><td>Ό</td><td>or</td><td>or</td><td>rt</td><td>or</td><td>or</td><td>rt</td><td>OR</td><td>rt</td><td>or</td><td>or</td><td>or</td><td>rt</td><td>or</td><td>Γ '</td><td> &lt;3</td><td>rt</td><td>\ D</td><td>Ό</td><td>or</td><td>OR</td><td>rt</td><td>θ '</td><td>to</td><td>or</td>

<td>Q</td><td></td><td></td><td> 1</td><td></td><td>rt</td><td> 1</td><td> 1</td><td>i</td><td> 1</td><td> 1</td><td> |</td><td> |</td><td>I</td><td> 1</td><td> 1</td><td></td><td> 1</td><td> 1</td><td>to</td><td> 1</td><td> 1</td><td>OI</td><td>to</td><td>oo</td><td>in</td><td>* P</td>

<td> ©</td><td></td><td></td><td>to</td><td>to</td><td>OR</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>ω</td><td>ω</td><td>ω</td><td>to</td><td>or</td><td>to</td><td>to</td><td>or</td><td>to</td><td>to</td><td>or</td><td>rt</td><td>in</td><td> 00</td><td></td>

<td> ©</td><td></td><td> 0*</td><td></td><td> 00</td><td>OR</td><td>τρ</td><td>ιη</td><td>or</td><td>rt</td><td>to</td><td> 00</td><td>to</td><td>"to*</td><td>rt</td><td>oo</td><td>or</td><td></td><td>in</td><td>or</td><td>-to·</td><td>M *</td><td>or</td><td>OR</td><td>or</td><td>in</td><td>rt</td>

<td>rt</td><td></td><td rowspan="2"></td><td rowspan="2">to</td><td rowspan="2">to</td><td>or</td><td> 00</td><td>to</td><td>or</td><td>to</td><td>to</td><td>rt</td><td>or</td><td>to</td><td>to</td><td>to</td><td>or</td><td>or</td><td>"to·</td><td>or</td><td>co</td><td></td><td>or</td><td>OR</td><td>ez&gt;</td><td>or</td><td>OR</td>

<td rowspan="2">OR</td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>or</td><td> •</td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td>

<td></td><td rowspan="2">1 T or 2 rt or</td><td rowspan="2">to</td><td>oo</td><td></td><td>I heard</td><td>OI</td><td> 01</td><td>rt</td><td>rt</td><td> 01</td><td>rt</td><td>I heard</td><td>co</td><td> 00</td><td></td><td>rt</td><td>rt</td><td></td><td>I heard</td><td>I heard</td><td></td><td></td><td></td><td></td><td></td>

<td> ©</td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td>or</td><td></td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td>

<td>Ί)</td><td></td><td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>r,</td><td></td><td>&gt; CQ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>* 0 h</td><td></td><td> ©</td><td> 00</td><td>in</td><td>to</td><td>or*</td><td>in</td><td>to</td><td>in</td><td>to</td><td> 00</td><td>OR</td><td> 00</td><td>t</td><td>«N</td><td>oo</td><td>in</td><td>• Φ</td><td>V0</td><td> 00</td><td>in</td><td>to</td><td>to</td><td>in</td><td> 00</td><td>to</td>

<td>4J</td><td></td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>rt</td><td>OR</td><td>rt</td><td>or</td><td>rt</td><td>or</td><td>in</td><td>OR</td><td>rt</td><td>or</td><td>or</td><td>or</td><td>or</td><td>'P</td><td>to</td><td>to</td><td>to</td>

<td> ©</td><td></td><td></td><td> 1</td><td>l</td><td></td><td></td><td></td><td></td><td>i</td><td> »</td><td></td><td></td><td> 1</td><td></td><td></td><td></td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td></td><td>or</td><td>or</td><td>to</td><td>or</td>

<td>I heard</td><td></td><td rowspan="2">CU</td><td>w</td><td>W</td><td>to</td><td>to</td><td>W</td><td>to</td><td>H</td><td>W</td><td>M</td><td>H</td><td>H</td><td>H</td><td>to</td><td>or</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>or</td><td>or</td><td> 00</td><td>to</td>

<td></td><td></td><td> 00</td><td></td><td>rt</td><td> 00</td><td>OI</td><td> ©*</td><td> 00</td><td>tP</td><td>&lt;P</td><td></td><td> 00</td><td>OR</td><td>to</td><td>or</td><td>to</td><td>to</td><td>or</td><td>to</td><td></td><td> 00</td><td>or</td><td>or</td><td>to</td><td>or</td>

<td>rM</td><td></td><td>J _.</td><td>θ '</td><td></td><td>OR</td><td>or</td><td>OI</td><td>in</td><td>rt</td><td>OI</td><td></td><td>OR</td><td> 00</td><td> 00</td><td> 00</td><td>or</td><td>to</td><td>to</td><td>in</td><td>in</td><td>or</td><td>in</td><td>or</td><td>or</td><td>or or</td><td>or or</td>

<td> ©</td><td></td><td>0 Ό rt rt</td><td>Cí</td><td>* P</td><td> 01</td><td>m</td><td>i — 1</td><td>to</td><td> 00</td><td>OI</td><td>rt</td><td></td><td>rt</td><td>I heard</td><td>Tp</td><td>or</td><td>to</td><td>rt</td><td>θ '</td><td>rt</td><td>rt</td><td> ©·</td><td>or</td><td></td><td>or</td><td>ΰ</td>

<td>Π</td><td></td><td> © ©</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>0 you</td><td></td><td> &gt; »</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>M</td><td>m</td><td> 01</td><td>to</td><td>I heard</td><td>OI</td><td>in</td><td>to</td><td> 00</td><td> 01</td><td>«Φ</td><td>I heard</td><td>OI</td><td>to</td><td> 0»</td><td> 01</td><td>to</td><td> 00</td><td>* P</td><td>OI</td><td>to</td><td> 00</td><td>to</td><td>to</td>

<td rowspan="2"> *0</td><td></td><td></td><td> 00</td><td>m</td><td> 0*</td><td>to</td><td>to</td><td>I heard</td><td></td><td> ©·</td><td>to</td><td>to</td><td> 00</td><td>rt</td><td> 01</td><td>to</td><td>or</td><td>to</td><td>or</td><td>OR</td><td>θ '</td><td>to</td><td>«P</td><td> 00</td><td>or</td><td>in</td>

<td>Q</td><td></td><td></td><td>in</td><td>in</td><td>to</td><td>σ&gt;</td><td>or</td><td>OI</td><td>in</td><td>to</td><td>'í ·</td><td>to</td><td>I heard</td><td>to</td><td>in</td><td>or</td><td>oo</td><td>rt</td><td>to</td><td>to</td><td>or</td><td>rt</td><td>to</td><td>to</td><td>to</td>

<td>jl</td><td></td><td></td><td>I heard</td><td>n</td><td></td><td>to</td><td>in</td><td>in</td><td>in</td><td>or</td><td>to</td><td>I heard</td><td>^ P</td><td>OR·</td><td>or</td><td>to</td><td>OI</td><td> 00</td><td>to</td><td>rt</td><td> 00</td><td>to</td><td> 00</td><td>r *</td><td>rt</td><td> ©«</td>

<td> 5</td><td></td><td></td><td>«P</td><td> 10</td><td></td><td>to</td><td>* p</td><td>to</td><td></td><td>θ '</td><td>to</td><td>or</td><td>in</td><td>θ '</td><td></td><td>in</td><td> 00</td><td>&lt;a *</td><td>in</td><td>rt</td><td>or</td><td>to</td><td>to</td><td>or</td><td>in</td><td>in</td>

<td> 1</td><td></td><td></td><td></td><td>OI</td><td> 00</td><td>'p</td><td>»Ρ</td><td>in</td><td>rt</td><td>-P</td><td>to</td><td>to</td><td>rt</td><td>to</td><td>rt</td><td>C</td><td>to</td><td> 00</td><td>to</td><td> 0»</td><td>or</td><td>rt</td><td> 00</td><td> 01</td><td>or</td><td>to</td>

<td>you 0 Q</td><td>§ Ή h</td><td>n and</td><td>m or</td><td>m or</td><td>• p or</td><td></td><td>* P or</td><td>OI or</td><td>&lt;P OR</td><td>to or</td><td>tP OR</td><td>to or</td><td>*to* or</td><td>I heard OR</td><td>^ í * OR</td><td>"to* or</td><td>to or</td><td>I heard or</td><td>M¹OR</td><td>to or</td><td>to or</td><td>rt i heard</td><td>to rt</td><td>to rt</td><td>© rt</td><td>rt</td>

<td></td><td> 0«</td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td> ©</td><td>to</td><td>to</td><td>to</td><td>to</td><td> 00</td><td> 00</td><td> 03</td><td>Γ-</td><td>to</td><td>rt</td><td></td><td>l&gt;</td><td>to</td><td>I heard</td><td> 00</td><td>or"</td><td>to</td><td> 00</td><td>to</td><td>to</td><td> 00</td><td> [</td><td>to</td><td>to</td>

<td></td><td></td><td>Ό</td><td>to</td><td>I heard</td><td>m</td><td>or</td><td>to</td><td>to</td><td>to</td><td>or</td><td></td><td>to</td><td>in</td><td>to</td><td>to</td><td>to</td><td>or</td><td>or</td><td>rt</td><td>to</td><td>to</td><td>or</td><td>σ »</td><td>in</td><td> ©·</td><td>OI</td>

<td></td><td></td><td></td><td> 10</td><td></td><td>in</td><td> 1</td><td>or</td><td>or</td><td>to</td><td> 00</td><td>to</td><td>to</td><td> 01</td><td>to</td><td></td><td>I heard</td><td>or</td><td> 1</td><td> ©·</td><td>or</td><td>in</td><td>r</td><td>to</td><td>I heard</td><td>or*</td><td>to</td>

<td></td><td></td><td></td><td>to</td><td>to</td><td>to</td><td>to</td><td>or</td><td>or</td><td>or</td><td>or</td><td>* P</td><td>rt</td><td>rt</td><td>or</td><td>or</td><td>M ·</td><td>"to¹</td><td>to</td><td>to</td><td>in</td><td>CO</td><td>to</td><td>or</td><td>rt</td><td>or</td><td>to</td>

<td></td><td></td><td rowspan="2">0 *&gt; i</td><td>to</td><td>M¹</td><td>or</td><td>OI</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>'to·</td><td>or</td><td> 00</td><td>OR</td><td>oo</td><td>or</td><td>in</td><td>or</td><td>OR</td><td>or</td><td>or</td>

<td></td><td></td><td>OR</td><td> 00</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>to</td><td>or</td><td>OR</td><td>or</td><td>I heard</td><td>or</td><td>OR</td><td>or</td><td>or</td>

<td>Q P</td><td></td><td>0 n rt O © -P</td><td>OR or</td><td>rt OR</td><td>or or</td><td>sP</td><td>or</td><td>or</td><td>or or</td><td>or or</td><td>or or</td><td>OR or</td><td>or or</td><td>or or</td><td>or or</td><td>or or</td><td>or or</td><td></td><td>or or</td><td>or or</td><td>or or</td><td></td><td>or or</td><td>OR or</td><td>or or</td><td>or or</td>

<td> &lt;</td><td></td><td>&gt; CQ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>to</td><td></td><td> ©</td><td></td><td>I heard</td><td>to</td><td>Γ</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>&lt;n</td><td>to</td><td> 00</td><td>to</td><td> 00</td><td>to</td><td>to</td><td>to</td><td>to</td>

<td>CU</td><td></td><td>Ό</td><td>rt</td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>to</td><td>or</td><td>or</td><td>to</td><td>or</td><td>or</td><td>I heard</td><td>to</td><td> 00</td><td>or</td><td>or</td><td>or</td><td>or</td><td>to</td>

<td></td><td></td><td></td><td>tn</td><td>Lfl</td><td>T</td><td></td><td></td><td></td><td></td><td> 1</td><td> 1</td><td></td><td>"to"</td><td> 1</td><td> 1</td><td>ao</td><td> 1</td><td> 1</td><td></td><td>oo</td><td>OJ</td><td> 1</td><td> 1</td><td rowspan="2">one to</td><td></td><td>^ P</td>

<td>OR</td><td></td><td rowspan="2">CU</td><td>to</td><td> 00</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>ω</td><td>W</td><td>rt</td><td>ω</td><td>to</td><td>in</td><td>to</td><td>to</td><td>or</td><td>or</td><td>or</td><td>to</td><td>to</td><td>to</td><td>i heard</td>

<td></td><td></td><td>or</td><td>to</td><td>or</td><td>&lt;n</td><td></td><td>or</td><td>• P</td><td>to</td><td>to</td><td>or</td><td>OR</td><td>to</td><td>rt</td><td>^ P</td><td> 00</td><td> 00</td><td>rt</td><td>to</td><td> 01</td><td>to</td><td>rt</td><td>to</td><td>in</td><td>rt</td>

<td> «.</td><td></td><td></td><td></td><td>I heard</td><td>or</td><td>OI</td><td>p</td><td>to</td><td></td><td>to</td><td>in</td><td>rt</td><td>OR</td><td></td><td>CO</td><td>rt</td><td>to</td><td></td><td>OR</td><td>to</td><td>or</td><td>to</td><td> 00</td><td>&lt;P</td><td>to</td><td>OR</td>

<td>H</td><td></td><td></td><td>or</td><td>P7</td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td>OR</td><td></td><td></td><td>OR</td><td>or</td><td>or</td><td></td><td></td><td></td><td></td><td>OR</td>

<td></td><td></td><td>0 Ό</td><td>or</td><td>OI</td><td>or</td><td>rt</td><td>&lt;p</td><td>τρ</td><td>OI</td><td>r&gt;</td><td>θ '</td><td> 01</td><td>or</td><td> 01</td><td>to</td><td>OR</td><td>to</td><td>rt</td><td>OR</td><td>or</td><td>or</td><td>θ '</td><td>sP</td><td>rt</td><td>to</td><td>OR</td>

<td>or</td><td></td><td>rt rt © ©</td><td>or</td><td>or</td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td>or</td><td></td><td></td><td>OR</td><td>or</td><td>or</td><td></td><td></td><td></td><td></td><td>or</td>

<td>to</td><td></td><td>&gt; s</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>0 or</td><td></td><td></td><td>r—</td><td>f *&gt;</td><td>to</td><td>OR-</td><td></td><td>in</td><td>OI</td><td>OI</td><td> 00</td><td>in</td><td>in</td><td>rt</td><td>to</td><td>qo</td><td></td><td> 01</td><td>rt</td><td></td><td>Tp</td><td>to</td><td> 00</td><td>OI</td><td>in</td><td>to</td>

<td></td><td></td><td></td><td>Γ</td><td>in</td><td>I heard</td><td>to</td><td>to</td><td> 0»</td><td></td><td>I heard</td><td>&lt;n</td><td>or</td><td> 00</td><td>to</td><td>co</td><td>to</td><td> 00</td><td>OR</td><td>in</td><td>to</td><td>θ '</td><td>rt</td><td></td><td>or</td><td>to</td><td>to</td>

<td></td><td></td><td></td><td>in</td><td> 00</td><td>or</td><td></td><td>or-</td><td>to</td><td>or</td><td>to</td><td>^ P</td><td>I heard</td><td>I heard</td><td></td><td>to</td><td> 00</td><td>-Φ</td><td>to</td><td>to</td><td>OI</td><td>to</td><td>θ '</td><td>θ '</td><td>to</td><td>to</td><td>to</td>

<td></td><td></td><td></td><td> 10</td><td>OI</td><td>or</td><td>I heard</td><td>or</td><td></td><td>to</td><td> 00</td><td>to</td><td></td><td>to</td><td></td><td>to</td><td>Γ *</td><td>I heard</td><td> 0*</td><td>or</td><td> 00</td><td>in</td><td>OR</td><td>to</td><td>to</td><td>* P</td><td> 01</td>

<td rowspan="2">or</td><td></td><td></td><td>CO</td><td>or</td><td>OI</td><td></td><td>θ '</td><td>OI</td><td>in</td><td>to</td><td>to</td><td>to</td><td>θ '</td><td>oo</td><td>θ '</td><td>C</td><td>or</td><td>in</td><td></td><td>to</td><td> 00</td><td></td><td>* P</td><td>to</td><td>or·</td><td> 00</td>

<td></td><td>J.</td><td>ro</td><td>or</td><td>to</td><td>to</td><td>in</td><td>θ '</td><td>or</td><td></td><td></td><td>rt</td><td>oo</td><td>I heard</td><td> ©·</td><td>to</td><td>to</td><td>rt</td><td>in</td><td>to</td><td> 00</td><td>to</td><td>to</td><td>rt</td><td> 00</td><td>to</td>

<td></td><td></td><td></td><td></td><td>LTI</td><td>or</td><td>to</td><td></td><td>OI</td><td>OI</td><td>I heard</td><td>or</td><td>Ί¹</td><td>θ '</td><td>to</td><td>m</td><td>to</td><td>I heard</td><td>to</td><td> 00</td><td> 00</td><td>to</td><td>or</td><td>-P</td><td>OI</td><td>* P</td><td>θ '</td>

<td>you</td><td></td><td>and to</td><td>to</td><td> 00</td><td>to</td><td>* P</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td></td><td>• «P</td><td>to</td><td>to</td><td></td><td>to</td><td>to</td><td> 00</td><td>&lt;n</td><td rowspan="2"></td><td>to</td><td> 00</td>

<td>0 Q &lt;J</td><td></td><td>g</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td>

<td></td><td></td><td> ©</td><td>m</td><td>OI</td><td>to</td><td>to</td><td></td><td>I heard</td><td>^ p</td><td>in</td><td>I heard</td><td>or-</td><td>to</td><td>to</td><td>to</td><td>to</td><td> 00</td><td>to</td><td>* P</td><td>to</td><td>co</td><td>rt</td><td> 00</td><td>θ '</td><td>to</td><td> 00</td>

<td>CQ</td><td></td><td>• rt</td><td> 0-</td><td>rp</td><td>to</td><td>in</td><td></td><td>or</td><td>or</td><td>OI</td><td>to</td><td>I heard</td><td>to</td><td>or</td><td>rt</td><td>rt</td><td>to</td><td>r »</td><td>I heard</td><td>to</td><td> 00</td><td>OR</td><td> 00</td><td>to</td><td> 00</td><td>in</td>

<td rowspan="2">CQ</td><td></td><td></td><td>I heard</td><td>^ P</td><td>to</td><td>r-</td><td>in</td><td>or</td><td>to</td><td>p</td><td>or</td><td>to</td><td> 00</td><td>in</td><td>in</td><td>sP</td><td>or·</td><td>to</td><td>to</td><td>I heard</td><td>rt</td><td>rt</td><td>in</td><td>θ '</td><td>θ '</td><td>rt</td>

<td></td><td rowspan="3">tr ._r &amp;</td><td>to</td><td>r ~</td><td>m</td><td>p-</td><td>in</td><td>to</td><td></td><td>OI</td><td>I heard</td><td>or</td><td>or</td><td>rt</td><td>to</td><td>to</td><td>OI</td><td>rt</td><td>to</td><td>in</td><td>to</td><td>OI</td><td>OI</td><td>OI</td><td>or</td><td>OI</td>

<td></td><td></td><td>in</td><td></td><td>m</td><td>to</td><td>to</td><td>rt</td><td> ©·</td><td>OI</td><td> [-“</td><td>rt</td><td> 00</td><td>or</td><td>in</td><td>in</td><td>in</td><td>OR</td><td> 00</td><td>'P</td><td>to</td><td>'P</td><td>rt</td><td>to</td><td>&lt;P</td><td>to</td>

<td></td><td></td><td>or</td><td> 00</td><td> 01</td><td>I heard</td><td>OI</td><td>OR</td><td>or</td><td>or</td><td>rt</td><td> 00</td><td>or</td><td>or</td><td>or</td><td>'φ</td><td>or</td><td>OR</td><td>σ&gt;</td><td>θ '</td><td>I heard</td><td>in</td><td>OR</td><td>«P</td><td>* P</td><td>&lt;P</td>

<td>rt</td><td></td><td>Ó M</td><td>rt</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>to</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>rt</td>

<td>© you</td><td></td><td>rt 0 © P</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td>

<td>Ή MJ</td><td></td><td>&gt; CQ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td> ©</td><td>'Φ</td><td>M *</td><td>m</td><td>I heard</td><td>in</td><td>t</td><td>rt</td><td></td><td>rt</td><td>in</td><td>σι</td><td>to</td><td>rt</td><td>OI</td><td>to</td><td>to</td><td>in</td><td>ςρ</td><td>to</td><td>t</td><td>to</td><td>to</td><td>to</td><td>θ '</td>

<td>4J</td><td></td><td>Ό</td><td>to</td><td>r ~ 1</td><td>or</td><td>to</td><td>in</td><td>or</td><td>OR·</td><td>Cí</td><td>to</td><td>to</td><td>θ '</td><td>or</td><td></td><td>co</td><td>in</td><td>or</td><td>to</td><td>or</td><td>to</td><td>or·</td><td>I heard</td><td>in</td><td>rt</td><td>to</td>

<td>you</td><td></td><td></td><td>to</td><td>t</td><td>ao</td><td></td><td>to</td><td>in</td><td>in</td><td>or"</td><td></td><td>to</td><td>OI</td><td> 1</td><td>to</td><td>to</td><td>-to¹</td><td> 1</td><td>θ '</td><td> 00</td><td>to</td><td>OI</td><td>or-</td><td>θ '</td><td>to</td><td>in</td>

<td> 3</td><td></td><td> 0&lt;</td><td>OI</td><td>to</td><td> 00</td><td>θ '</td><td>m</td><td>or</td><td>* P</td><td></td><td>to</td><td>rt</td><td>rt</td><td>to</td><td>to</td><td>to</td><td></td><td>to</td><td>OR</td><td>rt</td><td>or</td><td>to</td><td>or</td><td>to</td><td>OI</td><td>or-</td>

<td>CU</td><td></td><td></td><td>m</td><td>in</td><td> ©·</td><td>to</td><td>to</td><td>or</td><td>or</td><td>or</td><td>or</td><td>to</td><td>rt</td><td>to</td><td>or</td><td>to</td><td>rt</td><td>to</td><td>rt</td><td>in</td><td>to</td><td>rt</td><td>or</td><td>cit</td><td>rt</td><td>* P</td>

<td></td><td></td><td></td><td>in</td><td>to</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>to</td><td>OR</td><td></td><td>or</td><td>rt</td><td>OR</td><td>in</td><td>to</td><td>I heard</td><td>or</td><td>^ P</td><td>or</td><td>rt</td><td>OR</td><td>it is</td>

<td>rt V</td><td></td><td>0 Ό rt rt © ©</td><td>or or</td><td>or or</td><td>or or</td><td>or or</td><td>or or</td><td>or or</td><td>or or</td><td>or or</td><td></td><td>or or</td><td> 0.0</td><td></td><td>or or</td><td> 0.0</td><td>OR or</td><td></td><td>&lt;a · or</td><td>or or</td><td>or or</td><td>or or</td><td>or or</td><td>OR OR</td><td>OR</td><td>or or</td>

<td>fl 0</td><td></td><td>&gt; Ϊ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>QO</td><td>in</td><td>to</td><td>oo</td><td>«P</td><td>to</td><td>in</td><td>* P</td><td>CN</td><td>cu</td><td> [</td><td>in</td><td></td><td>Γ</td><td>to</td><td></td><td>OI</td><td>rt</td><td>to</td><td>or"</td><td>rt</td><td>to</td><td>to</td><td>to</td>

<td rowspan="2"> '0</td><td></td><td></td><td>in</td><td>or</td><td>to</td><td></td><td>to</td><td> 00</td><td></td><td>θ '</td><td> 0«</td><td>OR-</td><td>to</td><td>to</td><td> 00</td><td>or</td><td>rt</td><td>in</td><td> 00</td><td>in</td><td></td><td>in</td><td>-P</td><td>or</td><td>θ '</td><td>to</td>

<td></td><td></td><td>or</td><td>to</td><td>to</td><td>or</td><td> 00</td><td></td><td>to</td><td>to</td><td>in</td><td>to</td><td>to</td><td>to</td><td>or</td><td></td><td>rt</td><td>in</td><td>I heard</td><td>'P</td><td>θ '</td><td>in</td><td>'P</td><td>η</td><td>I</td><td>to</td>

<td></td><td></td><td></td><td>or</td><td></td><td>in</td><td>"to*</td><td>or</td><td>«P</td><td>OI</td><td>ao</td><td>to</td><td>or</td><td>or</td><td>I heard</td><td>or</td><td>or·</td><td>to</td><td>oo</td><td>to</td><td>or</td><td>to</td><td>Γ "</td><td>or</td><td>in</td><td>I heard</td><td>it is</td>

<td></td><td></td><td></td><td>m</td><td>rp</td><td>to</td><td>to</td><td>OI</td><td></td><td></td><td>rt</td><td>θ '</td><td>to</td><td>to</td><td> 00</td><td>co</td><td>to</td><td>I heard</td><td></td><td>to</td><td>or</td><td> 03</td><td>or</td><td>σ</td><td>in</td><td>θ '</td><td>in</td>

<td></td><td></td><td></td><td>r-</td><td> 0»</td><td>to</td><td>M *</td><td> &gt;</td><td>to</td><td> 00</td><td>rt</td><td></td><td>or-</td><td></td><td>rt</td><td>to</td><td>in</td><td>to</td><td> 00</td><td>in</td><td>or-</td><td>I heard</td><td></td><td>rn</td><td></td><td>to</td><td> 00</td>

<td>or 0 to</td><td></td><td>£ g</td><td>or</td><td>or</td><td>to or</td><td>to or</td><td>to or</td><td></td><td>to or</td><td>to OR</td><td>to or</td><td>to or</td><td>to or</td><td>to or</td><td>to or</td><td>to or</td><td>to or</td><td>"to· or</td><td>to or</td><td>to or</td><td>to or</td><td>I heard</td><td>θ ' rt</td><td>rt</td><td>0 « rt</td><td>rt</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>«Aj</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>OJ</td><td></td><td></td><td></td><td>rt</td><td></td><td></td><td></td><td rowspan="2">or</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>to</td><td></td><td>to</td><td></td><td>fQ</td><td>rt</td><td></td><td>I heard</td><td></td><td>rt</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>CQ</td><td></td><td></td><td rowspan="2">I heard two</td><td></td><td></td><td>cu</td><td>r-</td><td>J</td><td></td><td>OI</td><td>C</td><td> &lt;</td><td></td><td></td><td>rt</td><td></td><td></td><td>OR</td><td>OI</td><td>OI</td><td></td>

<td></td><td></td><td></td><td></td><td rowspan="2">or two</td><td>to</td><td></td><td> 2</td><td></td><td></td><td>CQ</td><td> 4</td><td>F</td><td>to</td><td>cu</td><td></td><td>C)</td><td>to</td><td></td><td>to</td><td>in</td><td>OI</td><td>OI</td><td></td><td>J</td><td> 01</td>

<td></td><td></td><td> 2</td><td>to</td><td> 2</td><td> 2</td><td>H</td><td>p</td><td>b</td><td>b</td><td>b</td><td>Π</td><td>b</td><td>rn</td><td></td><td>CU</td><td>w</td><td> □</td><td></td><td>b</td><td> £</td><td>X</td><td>or</td><td> 2</td><td>to</td><td>to</td>

<td></td><td></td><td>m</td><td>ω</td><td> 3</td><td>cu</td><td>CQ</td><td>CQ</td><td>CQ</td><td></td><td>OR</td><td>OR</td><td>Η</td><td>J</td><td> &lt;</td><td>cu</td><td>you</td><td>oi</td><td> 2</td><td>Y</td><td>OR</td><td>b</td><td>CU</td><td>Q</td><td>Q</td><td></td><td>fí</td>

<td></td><td></td><td>OR</td><td>OR</td><td>b</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>X</td><td>rt</td><td>rt</td><td>ii</td><td>OR</td><td>cu</td><td>cu</td><td>cu</td><td>cu</td><td>CQ</td><td> &gt;</td><td></td><td></td><td>Ei</td><td>OR</td><td>OR</td><td></td><td>D</td>

THE

Or i^-one ιη

IB table

<td colspan="2">you</td><td>Φ</td><td>kb</td><td>m</td><td>ω</td><td>ao</td><td>rd</td><td>rd</td><td>ct</td><td>kb</td><td>you*</td><td>GAVE</td><td>in</td><td>σι</td><td> 00</td><td>kb</td><td>kb</td><td>you*</td><td>ct</td><td>ko</td><td>a</td><td>ao</td><td>rd</td><td>oo</td><td>kb</td><td>a</td>

<td> 0</td><td></td><td>Ό</td><td>CD</td><td>rd</td><td>tn</td><td>co</td><td>or</td><td>tn</td><td>CO</td><td>or</td><td>P</td><td> 00</td><td>tn</td><td>or</td><td>a</td><td>OR</td><td>or</td><td>a</td><td>rd</td><td>or</td><td>UJ</td><td>σι</td><td>Ct</td><td>you*</td><td>r-</td><td>CJ</td>

<td>tea</td><td></td><td></td><td>you</td><td> &gt;</td><td>tn</td><td>you¹</td><td>tn</td><td>co</td><td>you*</td><td>I</td><td>ao</td><td>Ct</td><td>σι</td><td> 1</td><td>rd</td><td> 1</td><td> 1</td><td>in</td><td> 00</td><td> 1</td><td>rd</td><td>CD</td><td>you*</td><td>you</td><td>σι</td><td>co</td>

<td> (0</td><td></td><td rowspan="2"> 0*</td><td>or</td><td>OR</td><td>k0</td><td>σι</td><td>kb</td><td>m</td><td>m</td><td>you</td><td>ao</td><td>p</td><td>or</td><td>ω</td><td>&lt;b</td><td>you</td><td>you</td><td>you*</td><td>a</td><td>you</td><td>OR</td><td>you</td><td>OR</td><td>rd</td><td> 00</td><td> 00</td>

<td>Φ</td><td></td><td>or</td><td>OR</td><td></td><td></td><td></td><td>or</td><td>you*</td><td>p *</td><td>kb</td><td>rd</td><td>or</td><td>you*</td><td>or</td><td>c *</td><td>in</td><td>rd</td><td>σι</td><td>kb</td><td>or</td><td>a</td><td>OR</td><td>kb</td><td>a</td><td> 00</td>

<td></td><td></td><td rowspan="2">.. yes?</td><td>or</td><td>OR</td><td>or</td><td>CJ</td><td>or</td><td>or</td><td>or</td><td>in</td><td>OR</td><td>OR</td><td>in</td><td>p</td><td>or</td><td>tn</td><td>you*</td><td>rd</td><td>ct</td><td>ao</td><td>or</td><td>kb</td><td>OR</td><td>you</td><td></td><td>or</td>

<td rowspan="2">or</td><td rowspan="2"></td><td rowspan="2">OR</td><td rowspan="2">OR</td><td rowspan="2">or</td><td rowspan="2">or</td><td rowspan="2">or</td><td rowspan="2">or</td><td rowspan="2">or</td><td rowspan="2"></td><td rowspan="2">or</td><td rowspan="2">OR</td><td rowspan="2">or</td><td rowspan="2">rd</td><td rowspan="2">or</td><td rowspan="2">in</td><td rowspan="2">r-</td><td rowspan="2">OR</td><td rowspan="2">or</td><td rowspan="2">you*</td><td rowspan="2">or</td><td rowspan="2">or</td><td rowspan="2">OR</td><td rowspan="2">in</td><td rowspan="2">or</td><td rowspan="2">or</td>

<td></td>

<td>Φ</td><td></td><td>0 H rJ O</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>OR</td><td>or</td><td></td><td>or</td><td></td><td></td><td>OR</td><td></td><td></td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td>

<td> •0</td><td></td><td>you &lt;M</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>&gt; CO</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>'0 M</td><td></td><td>Φ</td><td>ib</td><td>in</td><td>σι</td><td>b</td><td>kb</td><td>kb</td><td>in</td><td>p</td><td>σι</td><td>you*</td><td>you*</td><td>rd</td><td>σι</td><td>F*</td><td>&lt;b</td><td>rd</td><td>you*</td><td>c-</td><td>kb</td><td> 00</td><td>kO</td><td>ao</td><td>ao</td><td>σι</td>

<td>4Λ</td><td></td><td> *0</td><td>OR</td><td></td><td>rd</td><td>σ</td><td>a</td><td>tn</td><td>or</td><td>or</td><td>σι</td><td>kb</td><td>kb</td><td>rd</td><td>oo</td><td>or</td><td>or</td><td>a</td><td>or</td><td>or</td><td>or</td><td></td><td>OR</td><td>in</td><td></td><td>Cl</td>

<td>Φ</td><td></td><td></td><td> 1</td><td></td><td></td><td>kb</td><td>or</td><td></td><td>you*</td><td> 1</td><td>you*</td><td>tn</td><td>in</td><td> 1</td><td>ct</td><td></td><td> 1</td><td>ct</td><td>σι</td><td></td><td></td><td>ct</td><td rowspan="2">one you</td><td>you</td><td>you</td><td>c-</td>

<td rowspan="2">you</td><td></td><td></td><td>ω</td><td>or</td><td>OR</td><td>p-</td><td>p ·</td><td>ct</td><td>ct</td><td>you</td><td>in</td><td>p</td><td>or</td><td>you</td><td>CD</td><td>you</td><td>you</td><td>rd</td><td>in</td><td>you</td><td>you</td><td>ct</td><td>m</td><td>in</td><td> 00</td>

<td></td><td></td><td>or</td><td>or</td><td>OR</td><td>p-</td><td>or</td><td>or</td><td>or</td><td>σι</td><td>you*</td><td>or</td><td>ib</td><td>in</td><td>OR</td><td>you*</td><td>r-</td><td> 00</td><td></td><td>a</td><td>a</td><td>ao</td><td>in</td><td>you</td><td>rd</td><td>a</td>

<td></td><td></td><td></td><td>you</td><td>or</td><td>or</td><td>rd</td><td>or</td><td>or</td><td>or</td><td>σι</td><td>or</td><td>or</td><td>CD</td><td>P</td><td>or</td><td>in</td><td>rd</td><td>OR</td><td>OR</td><td>co</td><td></td><td>kb</td><td>rd</td><td>kb</td><td>CO</td><td>or</td>

<td> T</td><td></td><td rowspan="2">0 Ό</td><td></td><td>or</td><td></td><td>OR</td><td>or</td><td>or</td><td></td><td></td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td></td><td></td><td>OR</td><td>kO</td><td></td><td></td><td>or</td><td></td><td>r *</td><td>OR</td><td>or</td>

<td>Φ</td><td></td><td rowspan="2">&lt;n</td><td></td><td>or</td><td></td><td></td><td></td><td>or</td><td>in</td><td></td><td></td><td></td><td>tn</td><td></td><td>you*</td><td>rd</td><td></td><td></td><td>kb</td><td>CD</td><td></td><td>on</td><td></td><td></td><td></td>

<td rowspan="2">to 0 η</td><td rowspan="2"></td><td rowspan="2">r-1 rd you ► x</td><td rowspan="2">or</td><td rowspan="2"></td><td rowspan="2">OR</td><td rowspan="2">or</td><td rowspan="2">or</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2">or</td><td rowspan="2">or</td><td rowspan="2">OR</td><td rowspan="2"></td><td rowspan="2">or</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2">OR</td><td rowspan="2">OR</td><td rowspan="2"></td><td rowspan="2"></td><td rowspan="2">or</td><td rowspan="2"></td><td rowspan="2">or</td><td rowspan="2">or</td><td rowspan="2">or</td>

<td></td>

<td></td><td></td><td></td><td>a</td><td></td><td></td><td>p »</td><td>σι</td><td>σι</td><td>kb</td><td>rd</td><td>p</td><td>tn</td><td>ct</td><td>kb</td><td>σι</td><td>ko</td><td>in</td><td>tn</td><td>rd</td><td>you*</td><td> 00</td><td>a</td><td>Γ</td><td> 00</td><td>a</td><td>a</td>

<td></td><td></td><td></td><td>CD</td><td>fl</td><td>rd</td><td>tn</td><td>rd</td><td> 00</td><td>p-</td><td>kb</td><td>kb</td><td>or</td><td>you*</td><td>in</td><td>ct</td><td>a</td><td>ao</td><td>CO</td><td>in</td><td>a</td><td>a</td><td>or</td><td>or</td><td>rd</td><td>a</td><td>or</td>

<td></td><td></td><td></td><td>σι</td><td>σι</td><td></td><td>in</td><td> 00</td><td>tn</td><td>rd</td><td>rd</td><td>kb</td><td>ct</td><td>or</td><td>oo</td><td>ct</td><td>you*</td><td></td><td> 00</td><td>kb</td><td>ct</td><td>ct</td><td>on</td><td>on</td><td>r</td><td>in</td><td>c-</td>

<td rowspan="2"> 0</td><td></td><td></td><td>you</td><td>m</td><td>rd</td><td>or</td><td>kb</td><td>ao</td><td>kb</td><td>tn</td><td>or</td><td>kO</td><td>kb</td><td>σι</td><td>co</td><td>ct</td><td>or</td><td>rd</td><td></td><td>in</td><td>a</td><td>in</td><td>a</td><td>in</td><td>kO</td><td> 00</td>

<td></td><td>Jj</td><td>or</td><td>or</td><td>OR</td><td>in</td><td>in</td><td>co</td><td>p-</td><td>σι</td><td>p</td><td>ao</td><td>CO</td><td>or</td><td>kb</td><td>ct</td><td>a</td><td>kb</td><td>in</td><td>rd</td><td>a</td><td>on</td><td>a</td><td>r</td><td>kb</td><td>you*</td>

<td></td><td></td><td>Q</td><td>CD</td><td>kb</td><td>you*</td><td>p ·</td><td>σι</td><td>r-</td><td>rd</td><td>p-</td><td>you*</td><td>tn</td><td>rd</td><td>p</td><td>σι</td><td>ao</td><td>rd</td><td></td><td>m</td><td></td><td>σι</td><td>I-</td><td>c-</td><td>a</td><td></td><td>ct</td>

<td>OR 0 OR</td><td>tt</td><td>H you</td><td>a or</td><td>in or</td><td>kO or</td><td>or</td><td>a or</td><td>tn or</td><td>kb OR</td><td> 0.4</td><td>ib or</td><td></td><td>p or</td><td>in or</td><td>a or</td><td>ct or</td><td>a or</td><td>ko or</td><td>σι or</td><td>in CD</td><td> 2.1</td><td>r- or</td><td> 1.8</td><td>Ol or</td><td>or</td><td> 0.4</td>

<td></td><td> 0«</td><td>OR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Φ</td><td>kb</td><td>a</td><td>tn</td><td>co</td><td></td><td>kb</td><td>c *</td><td>tn</td><td>kb</td><td>p</td><td>tn</td><td>p</td><td>p</td><td>a</td><td>kb</td><td> 01</td><td> 00</td><td>ct</td><td>rd</td><td>kb</td><td>kb</td><td>in</td><td>r&gt;</td><td>kb</td>

<td></td><td></td><td> •0</td><td>or</td><td>m</td><td>you*</td><td>tn</td><td>p »</td><td></td><td>or</td><td></td><td>ib</td><td>or</td><td>tn</td><td>or</td><td>σι</td><td>you*</td><td>or</td><td>a</td><td>a</td><td>σι</td><td>you*</td><td>or</td><td>rd</td><td>or</td><td>or</td><td>vo</td>

<td></td><td></td><td></td><td> 1</td><td>you*</td><td>k0</td><td>co</td><td>in</td><td>in</td><td>p *</td><td>or</td><td>ai</td><td>you*</td><td>σι</td><td> 1</td><td>ko</td><td>a</td><td> 1</td><td>a</td><td>you</td><td>r *</td><td>kb</td><td rowspan="2">you</td><td>Ct</td><td>rd</td><td>in</td><td>kb</td>

<td></td><td></td><td></td><td>M</td><td>or</td><td>on</td><td>σι</td><td></td><td>m</td><td>ct</td><td>or</td><td>σι</td><td>kb</td><td>ct</td><td>you</td><td>in</td><td>or</td><td>you</td><td>or</td><td>you</td><td>you*</td><td>or</td><td>in</td><td>OR</td><td>or</td><td>you</td>

<td></td><td></td><td rowspan="2">0 *&gt; 1 li flf</td><td>fd</td><td>or</td><td>or</td><td>co</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td> 00</td><td>or</td><td>or</td><td>tn</td><td>or</td><td>in</td><td>or</td><td>you</td><td>tn</td><td>ct</td><td>ct</td><td>OR</td><td>OR</td><td>or</td><td>σι</td>

<td></td><td></td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td>rd</td><td>or</td><td>or</td><td>in</td><td>or</td><td>ct</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>on</td>

<td></td><td></td><td></td><td></td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td>rd</td>

<td>and</td><td></td><td></td><td>sj *</td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>or</td><td>Ct</td><td></td><td>or</td><td>σι</td><td>or</td><td>or</td><td></td><td></td><td>you*</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>you</td><td></td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td>OR</td>

<td> &lt;4</td><td></td><td>&gt; co</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>to</td><td></td><td>Φ</td><td>r-</td><td>tn</td><td>tn</td><td>co</td><td>in</td><td>tn</td><td>tn</td><td>tn</td><td>ct</td><td>in</td><td>rd</td><td>OR</td><td>rd</td><td>kb</td><td></td><td>you*</td><td>σι</td><td>you*</td><td>CD</td><td>r-</td><td>a</td><td>P »</td><td>kb</td><td> 00</td>

<td>you</td><td></td><td>•you</td><td>or</td><td>or</td><td>you*</td><td>b</td><td>or</td><td>or</td><td>or</td><td>or</td><td>ao</td><td>rd</td><td>in</td><td>rd</td><td>rd</td><td>or</td><td>or</td><td>you*</td><td>or</td><td>in</td><td>in</td><td>or</td><td>or</td><td>or</td><td>or</td><td>Ct</td>

<td> 4</td><td></td><td></td><td> 1</td><td> 1</td><td>ct</td><td>ko</td><td> 1</td><td> 1</td><td></td><td> 1</td><td>you*</td><td>kb</td><td> 00</td><td> 1</td><td>you*</td><td>ao</td><td> 1</td><td>Cl</td><td>you</td><td>a</td><td>a</td><td></td><td></td><td rowspan="2">one you</td><td rowspan="2">you</td><td>on</td>

<td>or</td><td></td><td></td><td>co</td><td>fx |</td><td>CD</td><td>u&gt;</td><td>W</td><td>w</td><td>ω</td><td>you</td><td>in</td><td>p</td><td> 00</td><td>you</td><td>you*</td><td>or</td><td>you</td><td>rd</td><td>ko</td><td>rd</td><td>r *</td><td>you</td><td>you</td><td>m</td>

<td></td><td></td><td>you</td><td>σι</td><td>or</td><td>or</td><td>kD</td><td>CD</td><td>you*</td><td>rd</td><td> 00</td><td>ct</td><td>you*</td><td>or</td><td>you*</td><td>σι</td><td>rd</td><td>σι</td><td>rd</td><td>ko</td><td>OR</td><td>a</td><td>kb</td><td>or</td><td>rd</td><td>r-</td><td>in</td>

<td> «»</td><td></td><td></td><td rowspan="2">σι</td><td rowspan="2">a</td><td>or</td><td>in</td><td>tn</td><td>in</td><td>CO</td><td>p</td><td>or</td><td>in</td><td>OR</td><td>OR</td><td>rd</td><td>OR</td><td>ct</td><td>OR</td><td>you</td><td>Ct</td><td>or</td><td>OR</td><td>on</td><td>OR</td><td>kb</td><td>kb</td>

<td>H</td><td></td><td></td><td>or</td><td>or</td><td></td><td></td><td></td><td></td><td>or</td><td>or</td><td>or</td><td></td><td>OR</td><td>OR</td><td></td><td>or</td><td>a</td><td>OR</td><td>or</td><td></td><td></td><td></td><td></td><td>ct</td>

<td>you you or</td><td></td><td>0 Ό rd rd you</td><td>rd</td><td>r-</td><td>or</td><td>or or</td><td>rd</td><td>tn</td><td>in</td><td>«—I</td><td>or or</td><td>or or</td><td>or</td><td>kb</td><td>OR or</td><td>or or</td><td>you*</td><td> 0.0</td><td> 0.3</td><td>OR OR</td><td>or or</td><td>rd</td><td>you*</td><td>a</td><td>rd</td><td>or</td>

<td>to</td><td></td><td>&gt; s</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>0 OR</td><td></td><td></td><td></td><td>tn</td><td>co</td><td>kO</td><td>σι</td><td>rd</td><td>CD</td><td>kb</td><td>tn</td><td>you*</td><td>p</td><td>a</td><td>oo</td><td>kb</td><td>σι</td><td>CD</td><td>a</td><td>Ct</td><td> 00</td><td>in</td><td>kb</td><td>rd</td><td>in</td><td>in</td>

<td rowspan="2">to</td><td></td><td></td><td></td><td>σι</td><td>or</td><td>tn</td><td>σι</td><td></td><td>p »</td><td>σι</td><td>you*</td><td>ct</td><td>rd</td><td>you*</td><td>in</td><td>you*</td><td>Γ-</td><td>you*</td><td>r-</td><td>rd</td><td>kb</td><td>on</td><td>a</td><td>σι</td><td>rd</td><td>rd</td>

<td></td><td></td><td>Ct</td><td>or</td><td>σι</td><td>or</td><td>tn</td><td>kb</td><td>you*</td><td>ct</td><td> 00</td><td> 00</td><td>rd</td><td> 00</td><td>kb</td><td>rd</td><td>r-</td><td>rd</td><td>or</td><td>in</td><td>c-</td><td>kb</td><td>ko</td><td>you</td><td>OR</td><td>OR</td>

<td></td><td></td><td></td><td>Ct</td><td>r-</td><td>you*</td><td>ct</td><td>you*</td><td>you*</td><td>kb</td><td>or</td><td>or</td><td>or</td><td>you*</td><td>rd</td><td>you*</td><td>in</td><td> 00</td><td>σι</td><td>ao</td><td>σι</td><td>co</td><td>ct</td><td>rd</td><td>rd</td><td>OR</td><td>on</td>

<td> *2</td><td></td><td></td><td></td><td> 00</td><td>kO</td><td>CD</td><td>or</td><td>p-</td><td>in</td><td></td><td>ct</td><td>p</td><td>in</td><td>you*</td><td>σι</td><td>or</td><td>or</td><td>or</td><td>it is</td><td>σι</td><td>σι</td><td>or</td><td>rd</td><td>CJ</td><td>ci</td><td>in</td>

<td></td><td></td><td>Jj</td><td>m</td><td>kb</td><td>CD</td><td>p-</td><td>ct</td><td>in</td><td>CD</td><td>you*</td><td>tn</td><td>kb</td><td>rd</td><td>a</td><td>σι</td><td>in</td><td>r »</td><td>a</td><td>in</td><td>σι</td><td>on</td><td>a</td><td>OR</td><td>in</td><td>in</td><td>CD</td>

<td></td><td></td><td></td><td>b</td><td>Γ</td><td>r</td><td>kb</td><td>or</td><td>kb</td><td>you*</td><td>you*</td><td>kb</td><td>in</td><td>Ct</td><td>ct</td><td>kb</td><td>a</td><td>ko</td><td>or</td><td>r *</td><td>you</td><td>kb</td><td>a</td><td>rd</td><td>you*</td><td>r *</td><td>σι</td>

<td>if</td><td></td><td></td><td>a</td><td></td><td></td><td>r-</td><td>kb</td><td></td><td>kb</td><td>tn</td><td>kb</td><td>ib</td><td>P</td><td>tn</td><td>in</td><td>ko</td><td></td><td>Φ</td><td></td><td>you*</td><td>rd</td><td></td><td>σι</td><td>you*</td><td>you</td><td> 00</td>

<td></td><td></td><td></td><td></td><td>or</td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>to &lt;</td><td></td><td>g</td><td>or</td><td></td><td></td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td></td><td>OR</td><td>or</td><td>rd</td><td>Ct</td><td></td><td>rd</td><td>or</td><td>or</td><td>or</td>

<td></td><td></td><td>Φ</td><td>in</td><td>tn</td><td>P »</td><td>in</td><td>ao</td><td>CD</td><td>σι</td><td>rd</td><td>you*</td><td>ω</td><td>in</td><td>kb</td><td>σι</td><td>rd</td><td> 00</td><td>a</td><td>kb</td><td>in</td><td>kb</td><td>co</td><td>rd</td><td>you</td><td>ao</td><td>oo</td>

<td>co</td><td></td><td>•you</td><td>m</td><td></td><td>CD</td><td></td><td>in</td><td>OR</td><td></td><td>σι</td><td></td><td>p</td><td>or</td><td>or</td><td>ct</td><td>tn</td><td>t-</td><td>kb</td><td>CD</td><td> 00</td><td>kb</td><td>in</td><td>you*</td><td>ao</td><td>r »</td><td>on</td>

<td rowspan="3">co or</td><td></td><td></td><td>m</td><td>or</td><td>co</td><td>σι</td><td>ct</td><td>tn</td><td>σι</td><td>ao</td><td>ρ</td><td>σι</td><td>oo</td><td> 1</td><td>you*</td><td>F</td><td></td><td>you*</td><td>a</td><td>in</td><td>a</td><td>or</td><td>rd</td><td>on</td><td>you</td><td>or</td>

<td></td><td rowspan="3">cr μ} n</td><td>ct</td><td>ct</td><td>k0</td><td>you*</td><td>you*</td><td>in</td><td>you*</td><td>ao</td><td>in</td><td>a</td><td>rd</td><td>you</td><td>ct</td><td>you*</td><td>rd</td><td>ko</td><td>or</td><td>or</td><td>m</td><td>a</td><td>kb</td><td>ct</td><td>CD</td><td>c-</td>

<td></td><td>m</td><td>you</td><td></td><td>ct</td><td>in</td><td>ct</td><td>ct</td><td>ao</td><td>co</td><td>a</td><td>p</td><td>ct</td><td>ct</td><td>OR</td><td>OR</td><td>or</td><td>rd</td><td>kb</td><td>in</td><td> 00</td><td>OR</td><td>kb</td><td>rd</td><td></td>

<td></td><td></td><td>or</td><td>ct</td><td>ct</td><td>p »</td><td>or</td><td>ct</td><td>rd</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>p</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>a</td><td>OR</td><td>ct</td><td>you</td><td>or</td><td>a</td><td>Ct</td><td>ct</td>

<td>rd Φ you</td><td></td><td>0 h H 0 you · Μ</td><td>or or</td><td>or or</td><td> 0.0:</td><td>or or</td><td>or or</td><td>or or</td><td>OR OR</td><td> 0.0</td><td> 0'0</td><td>rd OR</td><td> 0.0</td><td></td><td> 0.0</td><td>or or</td><td> 0.0</td><td>or</td><td>or</td><td></td><td>or or</td><td> 0.0</td><td>or or</td><td>or or</td><td>OR OR</td><td>or or</td>

<td>-rl M4</td><td></td><td>&gt; co</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td>Φ</td><td>ao</td><td>P7</td><td>co</td><td>ko</td><td>you*</td><td>rd</td><td>ao</td><td>p</td><td>p</td><td>CO</td><td>rd</td><td>σι</td><td>kb</td><td>r-</td><td>kb</td><td>σι</td><td>you</td><td>ao</td><td>CO</td><td>&lt;b</td><td>rd</td><td>rd</td><td>a</td><td>on</td>

<td>JJ</td><td></td><td>•you</td><td>or</td><td>you</td><td>tn</td><td>oo</td><td>you*</td><td>you*</td><td>ao</td><td>m</td><td>or</td><td>rd</td><td>a</td><td>or</td><td> 00</td><td>r</td><td>or</td><td>ct</td><td>r-</td><td>m</td><td>CD</td><td>kb</td><td>r-</td><td>C-</td><td>CD</td><td>rd</td>

<td>you</td><td></td><td></td><td>or</td><td>m</td><td> 00</td><td>in</td><td>in</td><td>p-</td><td>P-</td><td>you*</td><td>ct</td><td>a</td><td>in</td><td>l</td><td>kb</td><td>rd</td><td> 1</td><td>ct</td><td>in</td><td>kb</td><td>OR</td><td>kp</td><td>CD</td><td>C *</td><td>or</td><td>OR</td>

<td>you</td><td></td><td>or,</td><td>m</td><td>C1</td><td>rd</td><td>kb</td><td>in</td><td>tn</td><td>rd</td><td>in</td><td>rd</td><td>CO</td><td>σι</td><td>you</td><td>rd</td><td>OR</td><td>you</td><td>ao</td><td>a</td><td>or</td><td>σι</td><td>a</td><td>or</td><td>in</td><td>or</td><td></td>

<td>you</td><td></td><td></td><td>or</td><td>tn</td><td>you*</td><td>kb</td><td>or</td><td>you*</td><td>ct</td><td></td><td>OR</td><td>σι</td><td>or</td><td>rd</td><td>OR</td><td>OR</td><td>kb</td><td>or</td><td>in</td><td>rd</td><td>you*</td><td>a</td><td>or</td><td>on</td><td>you</td><td>kb</td>

<td></td><td></td><td></td><td>or</td><td>or</td><td>or</td><td>ct</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>you*</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>σι</td><td>or</td><td>you*</td><td>Ct</td><td>or</td><td>rd</td><td>or</td><td>rd</td><td>or</td><td>or</td>

<td>rd</td><td></td><td>n «n</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td></td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td>or</td><td>r *</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>or</td>

<td> 0</td><td></td><td>H rd you</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>or</td>

<td>you 0</td><td></td><td>&gt; Ϊ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>or</td><td></td><td></td><td>co</td><td>kb</td><td>you*</td><td>you*</td><td>in</td><td>rd</td><td>σι</td><td>you*</td><td>you*</td><td>ct</td><td> 00</td><td>a</td><td>in</td><td>rd</td><td></td><td>a</td><td>in</td><td>a</td><td>ct</td><td> 00</td><td>Γ-</td><td>in</td><td>you</td><td>on</td>

<td rowspan="2">Ό</td><td></td><td></td><td>σι</td><td>CD</td><td> 00</td><td>tn</td><td>a</td><td>kb</td><td>P-</td><td>in</td><td>ct</td><td></td><td>p</td><td>Ct</td><td>I heard</td><td>kb</td><td>in</td><td>ao</td><td>you</td><td>oo</td><td>in</td><td>Cl</td><td>kb</td><td>r-</td><td>σι</td><td>in</td>

<td></td><td></td><td>kb</td><td>tn</td><td>ao</td><td>in</td><td>ct</td><td>rd</td><td>kb</td><td>σι</td><td>ao</td><td>ct</td><td>kb</td><td>σι</td><td>σι</td><td>ao</td><td>tn</td><td>or</td><td>kb</td><td>rd</td><td>ct</td><td>you</td><td>σι</td><td>co</td><td>CD</td><td>m</td>

<td></td><td></td><td></td><td></td><td></td><td>σι</td><td>in</td><td>ct</td><td>tn</td><td>rd</td><td>tn</td><td>P</td><td>in</td><td>in</td><td>or</td><td>co</td><td>ao</td><td></td><td>in</td><td>σι</td><td>OR</td><td>you*</td><td>kb</td><td>σι</td><td>on</td><td>or</td><td>Cl</td>

<td>you</td><td></td><td>Jj</td><td>b</td><td></td><td>ct</td><td>or</td><td>or</td><td>tn</td><td>you*</td><td>or</td><td>a</td><td>or</td><td>rd</td><td>kb</td><td>or</td><td>or</td><td>kb</td><td>rd</td><td>r-</td><td>or</td><td> 00</td><td>kb</td><td>you</td><td>you</td><td>r »</td><td>rd</td>

<td></td><td></td><td></td><td>or</td><td>co</td><td>p *</td><td>you*</td><td>σι</td><td>a</td><td>a</td><td>tn</td><td>ρ</td><td>kb</td><td>kb</td><td>ct</td><td>co</td><td>kb</td><td>rd</td><td>in</td><td>you*</td><td>on</td><td>kb</td><td>co</td><td>you*</td><td>c *</td><td>&lt;b</td><td>rd</td>

<td>ί! 0</td><td></td><td>5 you</td><td>a or</td><td> 0.6</td><td> 0.6</td><td>r- or</td><td>you* or</td><td>tn or</td><td> 0.5</td><td></td><td> 0.5</td><td> 0.6</td><td>S'0</td><td>tn or</td><td>SW</td><td>a or</td><td> 0.6</td><td> 0.5</td><td> 0.9</td><td> 1.4</td><td> 1.6</td><td> 0.6</td><td> 2.2</td><td> 0.6</td><td>kb or</td><td>C * OR</td>

<td> &lt;</td><td></td><td> »</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 03</td><td></td><td></td><td></td><td></td><td></td><td></td><td>CD</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td></td><td>tn</td><td></td><td></td><td></td><td></td><td>L »</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>rd</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>tn</td><td></td><td rowspan="2">in</td><td></td><td></td><td>you*</td><td></td><td>kb</td><td></td><td></td><td>in</td><td></td><td>rd</td><td>rd</td><td>you</td><td></td><td></td><td>kb</td><td></td><td> 4</td><td></td><td></td><td>rd</td>

<td></td><td></td><td></td><td>m</td><td></td><td>tn</td><td></td><td></td><td>Q</td><td></td><td>in</td><td>you</td><td>in</td><td>rd</td><td>ct</td><td>w</td><td>CU</td><td>you</td><td></td><td>ko</td><td>r-</td><td>you*</td><td> 00</td><td> «—</td><td rowspan="2">υ</td><td>DJ</td>

<td></td><td></td><td> 2</td><td>you</td><td>Ei</td><td></td><td> «3</td><td>you</td><td>co</td><td>B</td><td></td><td>you</td><td>rn</td><td>you</td><td>JP</td><td></td><td></td><td>rn</td><td>you</td><td></td><td>you</td><td>ct</td><td>you*</td><td>you</td><td>you</td><td>you</td>

<td></td><td></td><td>m</td><td> &gt;4</td><td>you</td><td>you</td><td> 2</td><td>OR</td><td>or</td><td> 3</td><td>R</td><td>you</td><td>r&gt;</td><td>rn</td><td></td><td>TO</td><td> 2</td><td>N</td><td> 2</td><td> &lt;3</td><td>His</td><td>you</td><td>you</td><td>OR</td><td>w</td><td>you</td><td>w</td>

<td></td><td></td><td>OR</td><td>OR</td><td> &amp;</td><td> 3</td><td></td><td>ω</td><td>you</td><td>OR</td><td></td><td>N</td><td>Q</td><td>ω</td><td>you</td><td></td><td></td><td></td><td></td><td></td><td>you</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>w</td><td>or</td>

or r4 in

IB table

<td>to</td><td></td><td> 0</td><td>S *</td><td> 04</td><td> 04</td><td></td><td>in</td><td> 10</td><td> 10</td><td></td><td> 04</td><td> 10</td><td> 00</td><td> 00</td><td>I heard</td><td>in</td><td> 10</td><td>co</td>

<td> 0</td><td></td><td>Ό</td><td>H</td><td>H</td><td> 04</td><td>or</td><td> 10</td><td>S ·</td><td> 10</td><td> 01</td><td>H</td><td> 04</td><td> 10</td><td> 00</td><td></td><td> 10</td><td>or</td><td> ^1</td>

<td>to</td><td></td><td></td><td>c-1</td><td>in</td><td> 10</td><td> 1</td><td> *·</td><td> 1*1</td><td> 10</td><td> 00</td><td>Rh</td><td>H</td><td>it is</td><td></td><td> |</td><td> 10</td><td> 1</td><td></td>

<td>you</td><td></td><td></td><td>OR</td><td>in</td><td>S &lt;</td><td>to</td><td>• Φ</td><td>or</td><td>m</td><td> 04</td><td>OR</td><td>OR</td><td>it is</td><td>in</td><td>to</td><td></td><td>to</td><td></td>

<td>φ</td><td></td><td></td><td>OR</td><td>in</td><td>P4</td><td></td><td>or</td><td>or</td><td> 10</td><td>m</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td> 10</td><td>or</td><td></td><td> 10</td>

<td>H</td><td></td><td></td><td>or</td><td>in</td><td>in</td><td> 10</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>r- |</td><td></td><td>or</td><td>s ·</td><td></td>

<td>or</td><td></td><td>Μ Φ 0 Jm</td><td>or</td><td>or</td><td> 04</td><td> 04</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td></td><td>or</td><td> 10</td><td>in</td>

<td> 0</td><td></td><td>HO</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td></td><td></td><td>or</td><td></td><td>or</td><td></td><td>or</td>

<td>Ό</td><td></td><td>(0 4J&gt; in</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>to</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> '0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Φ</td><td> 10</td><td> 04</td><td>P *</td><td> 00</td><td> 10</td><td> «3*</td><td>Item</td><td>i heard</td><td> 10</td><td> 10</td><td> 10</td><td> 10</td><td> ·*</td><td> 10</td><td></td><td>it is</td>

<td>4J</td><td></td><td>Ό</td><td>OR</td><td>in</td><td>i — l</td><td>OR</td><td> 00</td><td>co</td><td></td><td> *3*</td><td>or</td><td> 10</td><td> *3·</td><td>OR</td><td></td><td> 10</td><td>OR</td><td>s *</td>

<td> &lt;0</td><td></td><td></td><td rowspan="2">one to</td><td>H</td><td>s ·</td><td> 1</td><td>in</td><td>i-1</td><td>tn</td><td></td><td> 1</td><td>n</td><td>M ·</td><td> 10</td><td> 1</td><td></td><td> 1</td><td>OO</td>

<td>TO</td><td></td><td>TO</td><td></td><td>CO</td><td>to</td><td>t — 1</td><td>pH</td><td>or</td><td>or</td><td>to</td><td>or</td><td>OR</td><td> «3*</td><td>to</td><td>or</td><td>to</td><td>or</td>

<td></td><td></td><td></td><td> 04</td><td>OR</td><td>rf</td><td>in</td><td>OR</td><td>OR</td><td></td><td>m</td><td>in</td><td>or</td><td></td><td>P-</td><td></td><td>or</td><td>r&gt;</td><td>m</td>

<td></td><td></td><td>L ·</td><td>OI</td><td>in</td><td>r-1</td><td>in</td><td>OR</td><td>or</td><td>or</td><td>or</td><td> 00</td><td>or</td><td>OR</td><td>OR</td><td>in</td><td>or</td><td>co</td><td> 10</td>

<td>Φ</td><td></td><td>0 Ό</td><td>r-1</td><td>or</td><td>S ·</td><td>H</td><td>or</td><td>or</td><td>or</td><td>or</td><td>pH</td><td>or</td><td>OR</td><td>OR</td><td>i-1</td><td>or</td><td>p *</td><td>P *</td>

<td>_fi</td><td></td><td>10 you</td><td></td><td>or</td><td>OR</td><td></td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td>OR</td><td></td><td>or</td><td></td><td>or</td>

<td> 0</td><td></td><td>&gt; s</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>to</td><td></td><td></td><td> 04</td><td> 04</td><td>H</td><td>in</td><td>m</td><td> 01</td><td>* to &lt;</td><td> 01</td><td>m</td><td> 10</td><td> 00</td><td> 10</td><td> 10</td><td>m</td><td> 04</td><td>in</td>

<td> '0</td><td></td><td></td><td>C0</td><td>H</td><td> 10</td><td>m</td><td> 00</td><td>M</td><td> 10</td><td> 04</td><td> 04</td><td>in</td><td> 10</td><td>r *</td><td> 10</td><td>rd</td><td>it is</td><td></td>

<td></td><td> 0</td><td></td><td>OI</td><td>in</td><td>in</td><td>in</td><td>or</td><td>r-1</td><td> 01</td><td></td><td> 00</td><td> 04</td><td> 10</td><td>or</td><td>in</td><td>OI</td><td> 01</td><td> 10</td>

<td>or</td><td>• H</td><td></td><td>OR</td><td>or</td><td>rn</td><td> 10</td><td>f * 1</td><td> 00</td><td> 04</td><td>m</td><td> 10</td><td>CO</td><td>r-</td><td> 10</td><td>m</td><td>P »</td><td>or</td><td> 10</td>

<td> (0</td><td>h</td><td>4J</td><td>M *</td><td>m</td><td>s «</td><td>p-</td><td> 10</td><td>OI</td><td> 10</td><td>or</td><td>s *</td><td>Rh</td><td>i heard</td><td>OI</td><td>in</td><td>r-1</td><td> 10</td><td> 10</td>

<td></td><td> &lt;0</td><td>to</td><td>i—</td><td>M ·</td><td>in</td><td></td><td>OR</td><td> 10</td><td> &lt;3&lt;</td><td> 01</td><td>in</td><td> 10</td><td> 10</td><td> 00</td><td> 04</td><td> &lt;3·</td><td>it is</td><td> 10</td>

<td>or</td><td> 1</td><td>to</td><td> -3·</td><td></td><td> 00</td><td>Γ0</td><td> 10</td><td>in</td><td> 10</td><td>1Λ</td><td>m</td><td> 10</td><td> 10</td><td> 10</td><td>it is</td><td> 10</td><td>in</td><td> 01</td>

<td>0 Q</td><td>h</td><td>rt</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>pH</td><td>i — 1</td><td>or</td><td>OR</td><td>it is</td><td>OR</td>

<td>rt!</td><td>TO</td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>φ</td><td> 04</td><td>P *</td><td> 01</td><td> 10</td><td>in</td><td> 10</td><td>p *</td><td> 00</td><td> 10</td><td> 10</td><td></td><td></td><td> 10</td><td> 04</td><td>it is</td><td> 10</td>

<td></td><td></td><td> •0</td><td>i heard</td><td>in</td><td>or</td><td>OR</td><td>s ·</td><td>OR</td><td>in</td><td>P *</td><td>in</td><td>OR</td><td></td><td>H</td><td>in</td><td> 10</td><td> 04</td><td>rt</td>

<td> 0</td><td></td><td></td><td></td><td>p »</td><td>oo</td><td> 1</td><td></td><td> 1</td><td>m</td><td> 04</td><td>m</td><td> 1</td><td>r *</td><td>θ '</td><td>or-</td><td></td><td>it is</td><td>OR</td>

<td>Ό</td><td></td><td></td><td> 10</td><td>&lt;S</td><td> 10</td><td>to</td><td>or</td><td>to</td><td>or</td><td>m</td><td>or</td><td>to</td><td>i heard</td><td> «·</td><td>or</td><td>Γ *</td><td>il</td><td>OR</td>

<td> (0</td><td></td><td> 0* &gt;1</td><td>or</td><td>OR</td><td>in</td><td> 01</td><td>or</td><td>OI</td><td>or</td><td>or</td><td>or</td><td>pH</td><td> 10</td><td>it is</td><td>or</td><td>i — l</td><td>OR</td><td>OR</td>

<td>X&gt;</td><td></td><td>b Φ</td><td>or</td><td>OR</td><td></td><td> 04</td><td>or</td><td>i — l</td><td>or</td><td>or</td><td>or</td><td>P *</td><td>(Ό</td><td>t — 1</td><td>or</td><td>OR</td><td>OR</td><td></td>

<td>to</td><td></td><td>0 h</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td>

<td>you</td><td></td><td></td><td> •</td><td></td><td></td><td> «*»</td><td></td><td> 04</td><td></td><td></td><td></td><td>oo</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>• n</td><td></td><td> (0</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td></td>

<td> «&lt;</td><td></td><td>&gt; M</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Φ</td><td>Rh</td><td> 10</td><td>rt</td><td> 00</td><td> 10</td><td> 00</td><td> 10</td><td>in</td><td> 10</td><td>P *</td><td>pH</td><td> 10</td><td> 10</td><td>it is</td><td> 10</td><td> 10</td>

<td>TO</td><td></td><td>Ό</td><td>OI</td><td>OR</td><td>S *</td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>in</td><td>r — 1</td><td>or</td><td> 10</td><td>OR</td><td>or</td>

<td></td><td></td><td></td><td>in</td><td> 1</td><td>in</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td> 01</td><td> (*1</td><td>l</td><td> 10</td><td> 1</td><td> 1</td>

<td>OR</td><td></td><td></td><td>rn</td><td>M</td><td>in</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td> 10</td><td>i — l</td><td>to</td><td> 10</td><td>to</td><td>to</td>

<td></td><td></td><td>M</td><td>r4</td><td></td><td>'Φ</td><td> 04</td><td> 04</td><td> *»·</td><td> 10</td><td> 00</td><td>m</td><td>H</td><td> 04</td><td>I heard</td><td> 04</td><td></td><td>in</td><td></td>

<td> *</td><td></td><td></td><td>or</td><td>or</td><td>n</td><td>oo</td><td></td><td>r-1</td><td>m</td><td>pH</td><td>or</td><td> 10</td><td> &lt;*&gt;</td><td> 10</td><td>in</td><td>or</td><td>it is</td><td>co</td>

<td>H</td><td></td><td></td><td>or</td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 04</td><td>or</td><td></td><td>or</td><td></td><td></td>

<td>TO «</td><td></td><td>0 Ό</td><td>or</td><td>s ·</td><td>or</td><td> 10</td><td> 10</td><td> 1*1</td><td> 04</td><td>in</td><td> 04</td><td>M</td><td>OR</td><td>or</td><td>p-</td><td>or</td><td>pH</td><td>i — 1</td>

<td></td><td></td><td>you</td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>OR</td><td>or</td><td></td><td>or</td><td></td><td></td>

<td>to</td><td></td><td> &gt; £</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>or</td><td></td><td></td><td> 10</td><td>in</td><td>THE</td><td> 01</td><td>P-</td><td>ID</td><td>in</td><td>n</td><td>m</td><td>in</td><td> 10</td><td>r * i</td><td> 00</td><td> 00</td><td>m</td><td>co</td>

<td>to</td><td></td><td></td><td>in</td><td>or</td><td>in</td><td>in</td><td> 04</td><td>i — l</td><td> 04</td><td>or</td><td> 01</td><td>H</td><td>i — l</td><td>P-</td><td>or·</td><td>i — 1</td><td> «3*</td><td> 00</td>

<td>Ό</td><td></td><td></td><td> -3&lt;</td><td> 10</td><td></td><td>or</td><td>OI</td><td> 10</td><td>f * 1</td><td> 00</td><td>Γ-</td><td>ω</td><td> 00</td><td> 10</td><td> 10</td><td>or-</td><td>in</td><td>in</td>

<td>Ή</td><td></td><td></td><td>in</td><td></td><td>P-</td><td>or</td><td>in</td><td>OI</td><td>or</td><td> 10</td><td> 10</td><td> 10</td><td>or</td><td> *3»</td><td> «3*</td><td>m</td><td>or</td><td> 10</td>

<td>or</td><td></td><td> «</td><td>i-4</td><td>in</td><td>in</td><td>OI</td><td> 04</td><td>i — 1</td><td>sT</td><td>or</td><td>P-</td><td>it is</td><td>co</td><td>rl</td><td> 10</td><td>P-</td><td>or</td><td>p-</td>

<td> (0</td><td></td><td>JJ</td><td>in</td><td>or</td><td>or·</td><td>or</td><td>or</td><td>co</td><td></td><td> *3*</td><td>in</td><td> 01</td><td>or</td><td> 10</td><td> &lt;3·</td><td> 10</td><td>m</td><td>s ·</td>

<td></td><td></td><td>to</td><td> 00</td><td>m</td><td> 04</td><td>P&gt;</td><td>in</td><td>or</td><td>m</td><td>m</td><td></td><td>or</td><td>in</td><td> *3·</td><td> 10</td><td>s *</td><td>it is</td><td> 10</td>

<td>OR</td><td></td><td>w</td><td> 10</td><td>m</td><td>il</td><td>m</td><td>φ</td><td> •3*</td><td>í * 1</td><td>in</td><td>it is</td><td>it is</td><td></td><td>OI</td><td> 10</td><td></td><td> 10</td><td> 10</td>

<td>OR n</td><td></td><td></td><td>or</td><td>or</td><td>il</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>r-1</td><td>i-1</td><td>or</td><td>or</td><td>r-1</td><td>or</td>

<td></td><td></td><td>s</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>Φ</td><td> 00</td><td> 10</td><td></td><td>P *</td><td>in</td><td> 00</td><td> 10</td><td>in</td><td>co</td><td>it is</td><td> 10</td><td>P *</td><td> 10</td><td> 00</td><td>p '</td><td> 00</td>

<td>w</td><td></td><td>Ό</td><td>or</td><td> 00</td><td> 10</td><td> 04</td><td>p-</td><td>i — 1</td><td> 10</td><td> 04</td><td>r-</td><td>it is</td><td> 04</td><td> 10</td><td>or</td><td> 10</td><td>in</td><td>in</td>

<td>in</td><td></td><td></td><td>or</td><td>or</td><td> 10</td><td> 00</td><td> 01</td><td>in</td><td>«Φ</td><td>m</td><td>or·</td><td>r-</td><td> 10</td><td>it is</td><td>P '</td><td>it is</td><td> -3·</td><td>s ·</td>

<td>or</td><td></td><td> 0*</td><td>or</td><td>oo</td><td> 10</td><td>i-1</td><td>in</td><td> 04</td><td> 10</td><td>m</td><td>H</td><td> «3·</td><td>f * 1</td><td>iH</td><td>i — 1</td><td>s »</td><td> 10</td><td>co</td>

<td> 0«</td><td></td><td></td><td>or</td><td> 10</td><td> 04</td><td>i — l</td><td>i heard</td><td>P-</td><td>Γ0</td><td> 00</td><td>OR</td><td>rl</td><td> 00</td><td>P *</td><td>OR</td><td>H</td><td>i — l</td><td></td>

<td></td><td></td><td>h Φ</td><td></td><td>• Φ</td><td>in</td><td>OR</td><td>or</td><td>S *</td><td>or</td><td>it is</td><td>OR</td><td>OR</td><td>it is</td><td>i — 1</td><td>or</td><td>in</td><td>OR</td><td></td>

<td>rS</td><td></td><td>0 h</td><td>or</td><td>or</td><td></td><td>or</td><td>H</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td></td><td>or</td><td>or</td><td>or</td>

<td>you</td><td></td><td>r-1 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>to</td><td></td><td>you *&gt;</td><td></td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td>or</td>

<td>• H</td><td></td><td rowspan="2">&gt; in</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>«H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td>φ</td><td> 10</td><td>CS</td><td>or·</td><td>tn</td><td>P-</td><td> 10</td><td>P *</td><td>m</td><td> 10</td><td> 10</td><td>r-</td><td> 10</td><td>P-</td><td>it is</td><td></td><td> 10</td>

<td rowspan="2">to</td><td></td><td>Ό</td><td>o.</td><td>in</td><td>t — l</td><td>or</td><td>ID</td><td></td><td>M ·</td><td>or</td><td>or</td><td> 10</td><td> 00</td><td> 10</td><td>pH</td><td> *3*</td><td>s »</td><td>m</td>

<td></td><td></td><td> 1</td><td> 10</td><td> 04</td><td> 10</td><td> 04</td><td>in</td><td> 10</td><td>m</td><td>l</td><td>oo</td><td>t-1</td><td>OR</td><td></td><td>OR</td><td>or</td><td>it is</td>

<td></td><td></td><td>TO</td><td>to</td><td>in</td><td></td><td>OR</td><td>OI</td><td>or</td><td>m</td><td>Η</td><td>to</td><td>OR</td><td></td><td>p- |</td><td>OR</td><td> 10</td><td>rd</td><td> 10</td>

<td>TO</td><td></td><td></td><td>OI</td><td></td><td>in</td><td>OR</td><td>f * 1</td><td>in</td><td>or</td><td></td><td>P-</td><td>OR</td><td>or</td><td>Γ0</td><td>or</td><td> 01</td><td>or</td><td>it is</td>

<td></td><td></td><td></td><td>il</td><td>rt</td><td>r</td><td>or</td><td>in</td><td>ri</td><td>or</td><td>OR</td><td>you</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>and*)</td><td>or</td><td>or</td>

<td>Rh 0)</td><td></td><td>0 Ό</td><td> 1—1</td><td>OR</td><td> 10</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td></td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td>

<td rowspan="2">you 0 or you</td><td></td><td>you!&gt; 5</td><td></td><td>OR</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td></td><td>or</td><td></td><td>or</td><td></td><td>or</td><td>or</td><td>or</td>

<td></td><td></td><td> 04</td><td>m</td><td>&lt;n</td><td>in</td><td>in</td><td>in</td><td> 04</td><td> *»·</td><td> 00</td><td> 04</td><td> 10</td><td>i — l</td><td> 10</td><td></td><td>OI</td><td> 00</td>

<td>Ό</td><td></td><td></td><td>S ·</td><td>it is</td><td></td><td> 10</td><td> 10</td><td> 00</td><td>Lft</td><td> 01</td><td>it is</td><td>in</td><td>r-1</td><td>m</td><td> 1*1</td><td>or</td><td>i — 1</td><td>in</td>

<td>-H</td><td></td><td></td><td> •3*</td><td>i heard</td><td>m</td><td>in</td><td>I heard</td><td>m</td><td>OR</td><td>m</td><td> 10</td><td>or-</td><td>or</td><td>i — 1</td><td> 10</td><td></td><td>rl</td><td> 10</td>

<td>OR</td><td></td><td> •</td><td>i-4</td><td>it is</td><td>in</td><td>or</td><td>p ~</td><td> 10</td><td>OR</td><td>it is</td><td> 0*</td><td>i-1</td><td>r-</td><td>il</td><td>co</td><td> 04</td><td>rt</td><td>Φ</td>

<td>you</td><td></td><td>JJ</td><td>M ·</td><td> 10</td><td> 10</td><td> &lt;3·</td><td>p-</td><td>m</td><td> «·</td><td>oo</td><td>or-</td><td> 10</td><td> 01</td><td> 01</td><td> 10</td><td>OR</td><td>in</td><td>in</td>

<td>• rt</td><td></td><td>you</td><td>S »</td><td> 00</td><td>p-</td><td> 10</td><td> 01</td><td> &lt;3·</td><td></td><td></td><td>it is</td><td>in</td><td>or</td><td>s ·</td><td>H</td><td>or</td><td> 10</td><td>tl</td>

<td>or</td><td></td><td rowspan="2">H</td><td>in</td><td> 10</td><td>or</td><td></td><td> 10</td><td> 10</td><td>in</td><td> 10</td><td> 10</td><td> 10</td><td>P-</td><td>in</td><td> 10</td><td>P-</td><td>co</td><td> 10</td>

<td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>m</td><td></td><td></td><td>or</td><td>OR</td><td>pl</td><td></td><td>or</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>r-1</td><td>r-1</td><td>OR</td><td>or</td><td>iH</td><td>or</td>

<td></td><td></td><td>s</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>ffl</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>H</td><td></td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ΓΌ</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>TO</td><td></td><td></td><td> 04</td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td> &lt;</td><td>to</td><td></td><td></td>

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<td></td><td></td><td> %</td><td>TO</td><td>Ϊ4</td><td> 2</td><td>you</td><td></td><td> 10</td><td> 2</td><td> 2</td><td></td><td>n</td><td>S '</td><td>n</td><td> &lt;</td><td>TO</td><td> 0</td>

<td></td><td></td><td rowspan="2">to or</td><td>TO</td><td>f5</td><td>TO</td><td> 2</td><td> 2)</td><td> 2</td><td></td><td> 3</td><td> 2</td><td>TO</td><td> 5</td><td></td><td>or</td><td>H</td><td>g</td><td>p</td>

<td></td><td></td><td>Ω</td><td></td><td>ω</td><td>TO</td><td>H</td><td>^or</td><td>M</td><td></td><td>in</td><td>TO</td><td>in</td><td>in</td><td>in</td><td>in</td><td></td><td>TO</td>

or rH in

EXAMPLE 2: ALGORITHM DEVELOPMENT BASED ON THE DATA OF A

COMPLEMENTARY STUDY

The Cleveland Clinic (CC) supplementary study consists of three separate patient cohorts and analyzes for each cohort as described in Table 2. The first cohort (Table 2) includes men with high low risk (based on the AUA criteria) of cancer. Prostate of the Gene ID 09-002 study who underwent RP in CC between 1987 and 2004 and had diagnostic biopsy tissue available to CC. Cohorts 2 and 3 include men with clinically localized low and intermediate risk (based on the AUA criteria) of prostate cancer, respectively, who may have been reasonable candidates for active surveillance but who underwent radical prostatectomy (RP) within 6 months after the diagnosis of prostate cancer by biopsy. The main objective of Cohort 1 was to compare the molecular profile of the biopsy tissue with that of the radical prostatectomy tissue. The main objective of Cohorts 2 and 3 was to develop an indicator of multiple augmentation / reclassification genes in RP using biopsy tissue in patients with low to intermediate risk in diagnosis.

The matching biopsy samples were obtained for a subset of the patients (70 patients) of the gene identification study. Gene expression of the 81 selected genes and the 5 reference genes (ARF1, ATP5E, CLTC, GPS1, PGK1) were compared in the RP samples the biopsy tissue obtained from these 70 patients.

All 81 genes were evaluated in Cohorts 2 and 3 for association with augmentation and reclassification. The association between 81 genes and the increase and reclassification in Cohorts 2 and 3 are shown in Table 3. Values ​​p and the ratio of standardized possibilities are provided.

In this context, increase refers to an increase in the degree of Gleason from 3 + 3 or 3 + 4 at the time of the biopsy to greater than or equal to 3 + 4 at the time of RP. Increase 2 refers to an increase in the degree of Gleason from 3 + 3 or 3 + 4 at the time of the biopsy to greater than or equal to 4 + 3 at the time of RP.

TABLE 2

<td> #</td><td>from</td><td>Description of</td><td>Cohort</td><td># from</td><td>Goals</td><td></td><td></td>

<td colspan="2">Cohort</td><td></td><td></td><td>Patients</td><td></td><td></td><td></td>

<td> 1</td><td></td><td>Subset of</td><td>patients</td><td> 70</td><td colspan="2">• Comparison of</td><td>the</td>

<td></td><td></td><td>of the study ID</td><td>of Gen 09-</td><td></td><td>expression</td><td>gene of</td><td>the</td>

<td></td><td></td><td colspan="2">002 who underwent</td><td></td><td>sample of</td><td>biopsy with</td><td>the</td>

<td></td><td></td><td>RP in CC between</td><td>1987 and 2004</td><td></td><td>expression</td><td>gene</td><td>of the</td>

<td></td><td></td><td>and had</td><td>have gone from</td><td></td><td colspan="2">RP specimen (Objective</td><td>Co-</td>

<td></td><td></td><td>biopsy of</td><td>diagnosis</td><td></td><td>Primary)</td><td></td><td></td>

<td></td><td></td><td colspan="2">available in CC.</td><td></td><td>• To explore</td><td colspan="2">the Asociation</td>

<td></td><td></td><td></td><td></td><td></td><td>risky</td><td colspan="2">of recurrence</td>

<td></td><td></td><td>Patients of the</td><td>sample of</td><td></td><td colspan="2">after RP with</td><td>the</td>

<td></td><td></td><td colspan="2">stratified cohort</td><td></td><td>expression</td><td>gene of</td><td>the</td>

<td></td><td></td><td>original with</td><td>blocks of</td><td></td><td>sample of</td><td>biopsy and</td><td>the</td>

<td></td><td></td><td>I left you</td><td>biopsy</td><td></td><td>expression</td><td>gene</td><td>the</td>

<td></td><td></td><td>available</td><td></td><td></td><td>sample of</td><td>RP</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>• To explore</td><td colspan="2">the Asociation</td>

<td># from Cohort</td><td>Cohort Description</td><td># from Patients</td><td>goals</td>

<td></td><td></td><td></td><td>of the risk of recurrence after RP with gene expression</td>

<td> 2</td><td>Low Risk Patients of the CC database of patients who underwent biopsy, and then they underwent RP in CC between 1999 and 2010 All patients in the database who met the minimum tumor tissue criteria</td><td> 92</td><td>• Association between gene expression of the biopsy sample and the probability of increase / re-classification in the tissue obtained in prostatectomy • (Co-Primary Objective)</td>

<td> 3</td><td>Risk Patients Intermediate base CC data of patients who underwent biopsy, and then underwent RP in CC between 1999 and 2010 All patients in the database who met the minimum tumor tissue criteria</td><td> 75</td><td>• Association between gene expression of the biopsy sample and the probability of increase / re-classification in the tissue obtained in prostatectomy</td>

Several different models were explored to compare the expression between RP and biopsy samples. The genes were chosen based on the consistency of the expression between the RP and biopsy samples. Figures 2A-2E are the scatter plots showing the comparison of the normalized gene expression (Cp) for matching samples of each patient where the x axis is the normalized gene expression of the PGP RP (PGP) sample and the y axis is the normalized gene expression of the biopsy sample (BX). Figures 3A-3D graphical interval samples of gene expression of individual genes within each gene group in biopsy (BX) and PGP RP samples.

After evaluating the concordance of gene expression in the RP biopsy samples, the following algorithms (RS models) shown in Table 4 were developed where heights are determined using non-standardized, but standardized data. Some genes, such as SRD5A2 and GSTM2, which are within the group of cellular organization genes, were also evaluated separately and independent coefficients were assigned (see the other category in Table 4). In other cases, GSTM1 and GSMT2 were grouped as an oxidizing voltage group and a coefficient was assigned to this voltage group (see RS20 and RS22 models). Other genes, such as AZGP1 and SLC22A3, which are not found within any of the gene groups, were also included in certain algorithms (see the other category in Table 4). Additionally, the androgen gene group was established to include FAM13C, KLK2, AZGP1, and SRD5A2. Some genes such as BGN, SPARC, FLNC, GSN, TPX2 and SRD5A2 were formed in threshold before being evaluated in models. For example, normalized expression values ​​below 4.5 were set to 4.5 for TPX2 and normalized expression values ​​below 5.5 were adjusted to 5.5 for

SRD5A2.

Table 3; Association between the 81 genes and Increase and Reclassification in the Cohorts

Mi '-J cn |

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&lt;D

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&lt;· § «or o.

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<td>rd</td><td>OR</td><td>OR</td><td>rd</td><td>rd</td><td>OR</td><td>or</td><td>(N</td><td>or</td><td>rd</td><td>rd</td><td>OR</td><td>or</td><td>rd</td><td>rd</td><td>or</td><td>or</td><td>m</td><td>rd</td><td>CN</td><td> 04</td>

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<td>co</td><td>co</td><td>p</td><td>a</td><td>P</td><td>in</td><td>in</td><td>OR</td><td>co</td><td>rd</td><td>rd</td><td>CO</td><td>CO</td><td>or</td><td>in</td><td>or</td><td>or</td><td>or</td><td></td><td>or</td><td>OR</td>

<td>in</td><td>in</td><td>OI</td><td>OR</td><td>OR</td><td>p</td><td>rd</td><td>OR</td><td>co</td><td>OR</td><td>OR</td><td> 04</td><td>n</td><td>m</td><td> 04</td><td>in</td><td>m</td><td>or</td><td>OR</td><td>or</td><td>or</td>

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<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>(N</td><td></td><td>P</td><td>P</td><td>co</td><td></td><td> 00</td><td>m</td><td>in</td><td>co</td><td>CO</td><td>p</td><td>rd</td><td>a</td><td>or</td><td></td><td>co</td><td></td><td>a</td><td>in</td><td>co</td>

<td>a</td><td>OO</td><td>t</td><td>ro</td><td>in</td><td></td><td>CO</td><td> 04</td><td>p</td><td>OI</td><td>P</td><td>or</td><td> 04</td><td>or·</td><td>a</td><td> 04</td><td>or</td><td></td><td> 04</td><td>OI</td><td> 04</td>

<td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>x</td><td>X</td><td>X</td><td>X</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

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<td> 00</td><td>in</td><td>in</td><td>θ '</td><td> 00</td><td>in</td><td>in</td><td>CO</td><td>OO</td><td>CO</td><td>θ '</td><td>in</td><td>co</td><td>in</td><td> 00</td><td>CO</td><td>in</td><td></td><td>CO</td><td>co</td><td>co</td>

<td>OR</td><td>or</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>rd</td><td>co</td><td>t&gt;</td><td> 00</td><td>a</td><td>or</td><td>co</td><td>rd</td><td>m</td><td>or</td><td>r-</td><td>P</td><td>in</td><td> 00</td><td>OR</td><td>in</td><td>co</td><td>co</td><td>rd</td><td> ^3¹</td><td>^ p</td>

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<td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td>&lt;í</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

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<td>I heard</td><td>rd</td><td colspan="2">rd</td><td colspan="7"> 0</td><td colspan="3">or·</td><td> 0</td><td colspan="10"> 0</td>

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<td>OR</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>OR</td><td>Q</td><td>Q</td><td>Q</td><td> 0</td><td>ω</td><td>ω</td><td>b</td><td>b</td><td>b</td><td>b</td><td>b</td><td>b</td><td>b</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

in rd

Ό

Φ • you OU Η &lt;#&gt; you O ιη φ

<td>z — k</td><td>z — k</td><td>z—</td><td>z—.</td><td>z— \</td><td>z—,</td><td> &lt;—»</td><td>z — k</td><td>Z — k</td><td>Z—.</td><td>Z ~ k</td><td>Z — k</td><td>z — k,</td><td>z — k</td><td>Zk »</td><td>Z — k</td><td>Z — k</td><td>zk</td><td>Zk</td><td>Z — k</td><td>z — k</td><td>z — k</td><td>Z — k</td><td>z — k</td><td>Z—.</td>

<td>THE</td><td>in</td><td>or</td><td>ΓΊ</td><td>LT)</td><td>Γ-</td><td>THE</td><td>a</td><td> &gt;</td><td> 03</td><td>or</td><td></td><td>in</td><td>rd</td><td>OR</td><td>P *</td><td> 00</td><td>THE</td><td>P *</td><td> **</td><td>σι</td><td>THE</td><td> 03</td><td>M *</td><td>in</td>

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<td>* d *</td><td>in</td><td></td><td>a</td><td>LT1</td><td>σι</td><td>THE</td><td>THE</td><td> &lt;3*</td><td>t&gt;</td><td>THE</td><td>in</td><td>THE</td><td> 00</td><td>co</td><td>THE</td><td>THE</td><td>"to*</td><td>THE</td><td>in</td><td>in</td><td></td><td>or</td><td>or</td><td>THE</td>

<td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>rd</td><td>rd</td><td>OR</td>

you Φ h

<td>0 rd</td><td>faith Π</td><td>you *3</td><td>σι</td><td>p »</td><td>or</td><td>or</td><td>rd</td><td> 00</td><td> 00</td><td> 03</td><td>rd</td><td>OR</td><td> 00</td><td>in</td><td>OR</td><td> 03</td><td>rd</td><td>σι</td><td></td><td>rd</td><td>in</td><td>or</td><td>a</td><td>p-</td><td> 00</td><td>σι</td><td>tJ *</td>

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<td> ¡&gt;</td><td></td><td>There</td><td> •</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Φ</td><td> *0</td><td>you Q</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>rd</td><td>or</td><td>OR</td><td>OR</td><td>rd</td><td>or</td><td>rd</td><td>OR</td><td>rd</td><td>rd</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>rd</td><td>rd</td><td>or</td>

or cu

<td>4J</td><td></td><td>OR</td><td>THE</td><td>rd</td><td></td><td>LT)</td><td>p-</td><td>or</td><td>σι</td><td>r-</td><td>P-</td><td> 00</td><td>ed</td><td> 00</td><td>p-</td><td>THE</td><td>OR</td><td>σι</td><td>a</td><td> 03</td><td>rd</td><td>rd</td><td>σι</td><td>p-</td><td>rd</td><td>ΙΩ</td>

<td>you</td><td></td><td>in</td><td>M *</td><td>LD</td><td>or</td><td>in</td><td>P-</td><td>P-</td><td>in</td><td>or</td><td> 00</td><td>or</td><td>in</td><td>or</td><td>a</td><td>THE</td><td>in</td><td> 03</td><td>or</td><td>σι</td><td> 03</td><td>OR</td><td> 03</td><td>in</td><td>in</td><td>rd</td>

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<td> 3</td><td>you</td><td>or</td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>OR</td>

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<td> 0</td><td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>or</td><td>or</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td> 03</td><td>rd</td><td>rd</td><td>OR</td><td>rd</td><td>rd</td><td> 03</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td> 03</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td> 03</td><td> 03</td><td> 03</td><td>rd</td>

<td>you</td><td></td><td>• k</td><td>k.</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Φ</td><td>Φ</td><td>THE</td><td></td><td>rd</td><td>CO</td><td>p ~</td><td>THE</td><td>in</td><td>OI</td><td>CO</td><td>a</td><td> ^*</td><td> 03</td><td>OR</td><td>THE</td><td>rd</td><td> 00</td><td>σι</td><td>THE</td><td>You"</td><td>in</td><td>in</td><td>or</td><td> ^1*</td><td>rd</td><td>m</td>

<td> 9</td><td> •0</td><td>P *</td><td>THE</td><td>THE</td><td> 0»</td><td></td><td> 03</td><td>p *</td><td>THE</td><td>in</td><td>THE</td><td>P&gt;</td><td>rd</td><td> 00</td><td>σι</td><td>P ·</td><td></td><td>σι</td><td>in</td><td>THE</td><td>THE</td><td>THE</td><td>σι</td><td>rd</td><td>OR</td><td>a</td>

<td> 5</td><td></td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>rd</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>rd</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>rd</td><td>rd</td><td>or</td>

<td>0 or</td><td>H 0 rd</td><td>faith or</td><td>H you •you</td><td>rd</td><td></td><td>co</td><td>Tf *</td><td> 03</td><td>σι</td><td>a</td><td>σι</td><td>THE</td><td>&lt;to &lt;</td><td>or</td><td>in</td><td> 00</td><td>P ·</td><td>in</td><td>OR</td><td>OR</td><td>OR</td><td> 03</td><td>or</td><td>OR</td><td>a</td><td>in</td><td>P *</td><td>P ·</td>

<td>Φ i</td><td>Φ &gt;</td><td>Φ • 0</td><td>ig 4J</td><td>rd rd</td><td>σι OR</td><td>co or</td><td>rd rd</td><td>rd rd</td><td>00 rd</td><td>or rd</td><td>00 or</td><td>in or</td><td>in or</td><td>rd rd</td><td>P » rd</td><td>rd rd</td><td>in rd</td><td>OR rd</td><td>P · OR</td><td>a rd</td><td>00 or</td><td>σι or</td><td>or rd</td><td>σ or</td><td>ΓΏ rd</td><td>00 rd</td><td>You* rd</td><td>P- OR</td>

<td></td><td>Φ •you</td><td> 03</td><td>CQ Φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

Pi

<td></td><td> 03</td><td>CO</td><td>in</td><td>or</td><td>rd</td><td> 03</td><td>or</td><td> 00</td><td>in</td><td> 00</td><td> 03</td><td>in</td><td>a</td><td>or</td><td>co</td><td> 00</td><td>THE</td><td>rd</td><td>THE</td><td> 01</td><td>in</td><td>rd</td><td>m</td><td>P</td><td>P</td>

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<td>^Ό 0</td><td>THE</td><td> 00</td><td>M »</td><td>a</td><td>a</td><td>OR</td><td>P</td><td>a</td><td>or</td><td>P</td><td>THE</td><td>OR</td><td></td><td>or</td><td> 00</td><td>or</td><td>or</td><td> 03</td><td>THE</td><td>σι</td><td>in</td><td>rd</td><td>OR</td><td>OR</td><td>rd</td>

<td> rt</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td>

<td></td><td>Φ</td><td></td><td>THE</td><td>or</td><td> *3*</td><td>p</td><td>in</td><td> 00</td><td>THE</td><td> 00</td><td>a</td><td>in</td><td>YOU"</td><td>σι</td><td> 01</td><td>a</td><td>P</td><td>in</td><td>rd</td><td></td><td>CO</td><td>a</td><td>í¹</td><td>σι</td><td>P</td><td>r *</td><td>co</td>

<td>Φ</td><td>Ό</td><td></td><td>in</td><td>THE</td><td>THE</td><td>rd</td><td></td><td>P</td><td>in</td><td>M ·</td><td>rd</td><td> 03</td><td>in</td><td>p</td><td>a</td><td> «4»</td><td>THE</td><td> 03</td><td> 03</td><td>in</td><td>OR</td><td>in</td><td> 03</td><td>a</td><td> 00</td><td>in</td><td>or</td>

<td>Ό</td><td>0 4J</td><td>H</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

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<td>σι</td><td></td><td></td><td>p</td><td> 00</td><td> 00</td><td>THE</td><td>P</td><td>σι</td><td>P</td><td> 00</td><td>THE</td><td>THE</td><td>P</td><td>σι</td><td> 00</td><td>P</td><td> 00</td><td>THE</td><td>THE</td><td>p</td><td>a</td><td>P</td><td>THE</td><td> 00</td><td>σι</td><td>P&gt;</td><td>a</td>

<td></td><td></td><td></td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>OR</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td>

or ¡ii «-S

Ι · 3ΐ &lt;S

<td>or</td><td>P-</td><td>OR</td><td>THE</td><td>a</td><td>OR</td><td>OR</td><td>σι</td><td></td><td>or</td><td>P-</td><td>rd</td><td>THE</td><td>THE</td><td>rd</td><td>OR</td><td>σι</td><td>co</td><td>co</td><td>σι</td><td>rd</td><td></td><td>THE</td><td>OR</td><td>CO</td>

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<td>rd</td><td>rd</td><td>rd</td><td>OR</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>OR</td><td>or</td><td>or</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>rd</td><td>rd</td><td>rd</td><td>OR</td>

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<td></td><td></td><td></td><td></td><td>CS</td><td></td><td></td><td></td><td>one m</td><td> 1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td> 1</td><td></td><td></td><td></td><td>I</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>to 0</td><td>X CM H *</td><td>co it is CJ</td><td></td><td></td><td>« you 4J</td><td>ro you it is cj</td><td></td><td></td><td>on-</td><td></td><td></td><td>two i heard</td><td></td><td>on-</td><td>X CM H 4</td><td>P0 &lt;</td><td></td><td>you 0</td><td>it is</td><td>it is</td><td></td><td>ton-</td><td></td><td>it is g</td><td></td><td></td>

<td></td><td></td><td></td><td>♦ rt</td><td></td><td>ri</td><td></td><td></td><td>in</td><td>Γ 1</td><td></td><td></td><td>• rl</td><td></td><td></td><td>or</td><td></td><td>• rl</td><td>you*</td><td>it is</td><td></td><td>• H</td><td>X</td><td> 2</td><td></td><td>you</td><td></td><td>in</td><td></td><td></td>

<td></td><td></td><td></td><td>4J</td><td>rS</td><td>, τ</td><td></td><td></td><td></td><td>η</td><td></td><td></td><td>4J</td><td></td><td></td><td> *</td><td></td><td>4J</td><td>i — l</td><td>it is</td><td></td><td>JJ</td><td>CM</td><td>H</td><td></td><td>Cs</td><td>it is</td><td>OR</td><td></td><td></td>

<td></td><td></td><td></td><td>you</td><td></td><td>W</td><td></td><td></td><td></td><td>in</td><td></td><td></td><td>you</td><td></td><td></td><td></td><td></td><td>you</td><td></td><td>t&gt;</td><td></td><td>you</td><td>AND-"</td><td>in</td><td></td><td>OR)</td><td>X</td><td> 4</td><td></td><td></td>

<td></td><td></td><td></td><td>kl</td><td></td><td> *</td><td></td><td></td><td></td><td> 4</td><td></td><td></td><td>Cs</td><td></td><td></td><td>or</td><td></td><td>Me</td><td>OR</td><td></td><td></td><td></td><td> 4</td><td>OR</td><td></td><td>• rl</td><td>CM</td><td>tn</td><td></td><td></td>

<td></td><td></td><td></td><td>σι</td><td></td><td>r-</td><td></td><td></td><td></td><td> 00</td><td></td><td></td><td>in</td><td></td><td>I heard</td><td></td><td></td><td>in</td><td></td><td>in</td><td></td><td>σι</td><td>to</td><td> 4</td><td></td><td> 2</td><td></td><td>you*</td><td></td><td></td>

<td></td><td></td><td></td><td>• rt</td><td></td><td>or</td><td></td><td>W</td><td>θ</td><td>or</td><td></td><td></td><td>-rl</td><td></td><td></td><td>or</td><td></td><td>• r |</td><td></td><td> 4</td><td></td><td>• rl</td><td>rS</td><td>you·</td><td></td><td> 4</td><td> 4</td><td>pS</td><td></td><td></td>

<td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td>LM</td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td> *</td><td></td><td></td><td> 2</td><td></td><td>r</td><td></td><td> 2</td><td></td><td>rS</td><td></td><td> 00</td><td>you*</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> *</td><td></td><td>or</td><td></td><td> *</td><td></td><td>or</td><td></td><td></td><td> 4</td><td></td><td>it is</td><td></td><td></td><td> 4</td><td></td><td>or</td><td></td><td> 4</td><td>OR</td><td></td><td></td><td>&lt;x »</td><td>(You</td><td>OR</td><td></td><td></td>

<td></td><td></td><td></td><td>σ</td><td></td><td></td><td></td><td>THE</td><td></td><td></td><td></td><td></td><td> &lt;0</td><td></td><td>or</td><td></td><td></td><td>CO</td><td></td><td></td><td></td><td>you*</td><td></td><td>OR</td><td></td><td>CO</td><td>OR</td><td> 1</td><td></td><td></td>

<td></td><td></td><td></td><td>pH</td><td></td><td></td><td></td><td>you*</td><td></td><td></td><td></td><td></td><td>&lt;S</td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td>or</td><td> +</td><td>it is</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>it is</td><td>or</td><td>OR</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>OR</td><td></td><td>rS</td><td> &lt;</td><td>or</td><td>it is</td><td>pH</td><td></td><td></td><td>OR</td><td></td><td> +</td><td>rS</td><td> 4</td><td>or</td><td></td><td>H</td><td></td><td>OR</td><td></td><td>rS</td><td>you</td><td></td><td> +</td><td>CM</td><td>tn</td><td></td>

<td>Q</td><td></td><td></td><td></td><td> +</td><td>CM</td><td>tn</td><td></td><td>X</td><td>CM</td><td>tn</td><td></td><td></td><td> +</td><td>it is</td><td>CM</td><td>tn</td><td></td><td> +</td><td>CM</td><td>tn</td><td></td><td> +</td><td>CM</td><td>tn</td><td></td><td></td><td rowspan="2">OR X</td><td>Q</td><td></td>

<td>s</td><td></td><td></td><td>s</td><td></td><td>OR</td><td>or</td><td>s</td><td>CM</td><td>in</td><td>Y</td><td></td><td>s</td><td>rt</td><td>X</td><td>OR</td><td>that</td><td> 2</td><td></td><td>and¹)</td><td>Q</td><td>X</td><td></td><td>fí</td><td>that</td><td>Π</td><td>in</td><td> 2</td><td></td>

<td>4J</td><td></td><td></td><td>OR</td><td>in</td><td>N</td><td> 2</td><td> □</td><td>H</td><td>n</td><td> 2</td><td></td><td>or</td><td>in</td><td>CM</td><td>N</td><td> 2</td><td>OR</td><td>in</td><td>K</td><td> 2</td><td>or</td><td>in</td><td>N</td><td> 2</td><td>ω</td><td> 0«</td><td> &lt;</td><td>in</td><td></td>

<td>• H</td><td></td><td></td><td>w</td><td>CM</td><td>rtí</td><td>in</td><td>w</td><td> *</td><td></td><td>in</td><td></td><td>W</td><td>CM</td><td>H</td><td>you</td><td>in</td><td>w</td><td>CM</td><td></td><td>in</td><td>w</td><td> 0«</td><td></td><td>in</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td></td>

<td>h</td><td></td><td></td><td> *</td><td> *</td><td> *</td><td> *</td><td> 4</td><td> 00</td><td> *</td><td> *</td><td></td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td> 4</td><td>tn</td><td>it is</td><td>to</td><td></td><td></td>

<td> 0</td><td></td><td></td><td> 00</td><td>ro</td><td>ao</td><td>r-1</td><td>it is</td><td>p4</td><td>co</td><td>you·</td><td></td><td>ro</td><td>tn</td><td>r ~</td><td>t-</td><td>σ&gt;</td><td>it is</td><td>OR</td><td>and*</td><td>r ~</td><td>it is</td><td>tn</td><td></td><td>ao</td><td>CO</td><td>tn</td><td>it is</td><td>in</td><td></td>

<td>σ</td><td></td><td></td><td> \0</td><td>you*</td><td>pH</td><td>co</td><td>THE</td><td></td><td>pH</td><td>ro</td><td></td><td>r *</td><td>you·</td><td>pH</td><td>H</td><td>it is</td><td>in</td><td>co</td><td>pH</td><td>it is</td><td>r-</td><td>you*</td><td>pS</td><td>it is</td><td>r-</td><td>ro</td><td>it is</td><td>co</td><td></td>

<td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> &gt;&lt;</td><td></td><td></td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td> +</td><td>OR</td><td>or</td><td></td><td>or</td><td>or</td><td>OR</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>to</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>or</td><td>or</td><td>or</td><td>or</td><td></td>

<td></td><td></td><td></td><td>CS</td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td>it is</td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>you</td><td></td>

<td></td><td></td><td></td><td>CS</td><td>it is</td><td></td><td></td><td></td><td> 2</td><td></td><td>it is</td><td>it is</td><td>p4</td><td></td><td></td><td></td><td></td><td>it is</td><td>it is</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 41</td><td></td>

<td></td><td></td><td></td><td> (1</td><td>&lt;a¡</td><td></td><td></td><td></td><td>P</td><td></td><td>OR</td><td></td><td>CM</td><td>ΙΠ</td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>or</td><td>Lf)</td><td></td><td></td><td></td><td>in</td><td></td><td>J</td><td>the</td><td>in</td><td>OR</td><td></td><td></td><td></td><td></td><td>tn</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 0</td><td></td>

<td></td><td></td><td></td><td>W</td><td>OR</td><td></td><td></td><td>i heard</td><td>OR</td><td></td><td>Ui</td><td>Q</td><td>N</td><td> 2</td><td></td><td></td><td></td><td>in</td><td>that</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Ί1</td><td>x- ^</td>

<td></td><td></td><td></td><td> «.</td><td> 2</td><td></td><td></td><td>m</td><td> +</td><td></td><td></td><td> 2</td><td>"you</td><td>in</td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td> «.</td><td>w</td><td>it is</td><td></td><td> »</td><td> «.</td><td>it is</td><td>you</td><td>i — 1</td>

<td>to</td><td></td><td></td><td>t “l</td><td>ω</td><td></td><td></td><td>you</td><td>p.m</td><td></td><td>H</td><td>in</td><td></td><td></td><td></td><td></td><td></td><td>pH</td><td>w</td><td></td><td></td><td>pH</td><td>it is</td><td> 4</td><td></td><td>pS</td><td>it is</td><td></td><td>g</td><td>you</td>

<td> 0</td><td></td><td></td><td>tM</td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td>CM</td><td> 2</td><td>in</td><td></td><td>CM</td><td> 2</td><td>in</td><td>Y</td><td>d</td>

<td>h</td><td></td><td></td><td>n</td><td> «.</td><td></td><td></td><td>jj</td><td>H</td><td></td><td>ro</td><td> «.</td><td></td><td> 9</td><td></td><td></td><td></td><td>n</td><td> *</td><td></td><td></td><td>OR</td><td></td><td>that</td><td></td><td>Γ *)</td><td>Y</td><td>Y</td><td>OR</td><td>Λ</td>

<td>4J</td><td></td><td></td><td>(M</td><td>m</td><td></td><td></td><td>in</td><td>Saw</td><td></td><td>N</td><td>Γ0</td><td>X</td><td>I heard</td><td></td><td></td><td></td><td>N</td><td>fO</td><td></td><td></td><td>N</td><td>in</td><td> 2</td><td></td><td>N</td><td>tn</td><td> 2</td><td>* H</td><td>g</td>

<td>OR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td>* C</td><td></td><td>OR)</td><td></td><td></td><td></td><td> &lt;</td><td> &lt;</td><td></td><td></td><td></td><td>OR</td><td>in</td><td></td><td>rt¡</td><td>OR</td><td>in</td><td></td><td> 3</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>CO</td><td></td><td> \</td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>pH</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 5*</td><td></td><td>it is</td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>rx</td><td></td><td>X</td><td></td><td></td>

<td>you</td><td></td><td></td><td> +</td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td>Cm</td><td></td><td></td><td></td><td></td>

<td>to&gt;</td><td></td><td></td><td>or</td><td>it is</td><td></td><td></td><td>or</td><td>it is</td><td></td><td></td><td></td><td>or</td><td>it is</td><td></td><td></td><td></td><td>or</td><td>it is</td><td></td><td></td><td>or</td><td>it is</td><td></td><td></td><td> 4</td><td></td><td> 2</td><td></td><td></td>

<td> 01</td><td></td><td></td><td>m</td><td> \</td><td></td><td></td><td>CO</td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td></td><td></td><td> 4</td><td></td><td></td>

<td> 0</td><td>x- ^</td><td></td><td>rS</td><td>x- ^</td><td></td><td></td><td>p4</td><td></td><td></td><td></td><td></td><td>H</td><td>x- ^</td><td></td><td></td><td></td><td>pH</td><td></td><td></td><td></td><td>rS</td><td></td><td></td><td></td><td>to</td><td></td><td> 00</td><td></td><td></td>

<td>M • d</td><td>4 0Ϊ</td><td></td><td> §</td><td> 2</td><td></td><td></td><td></td><td>it is X</td><td></td><td></td><td></td><td> §</td><td>it is X</td><td></td><td></td><td></td><td> §</td><td>it is X</td><td></td><td></td><td colspan="2">S 2</td><td></td><td></td><td>it is</td><td></td><td>tn pS</td><td></td><td></td>

<td>you</td><td>Q &lt;</td><td></td><td>Cu</td><td>J</td><td></td><td></td><td>Cm</td><td>J</td><td></td><td></td><td></td><td>Cm</td><td>TO</td><td></td><td></td><td></td><td> £</td><td>J</td><td></td><td></td><td>Cm</td><td>TO</td><td></td><td></td><td>H</td><td> +</td><td></td><td></td><td></td>

<td> &lt;3</td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td>or</td><td>it is</td><td>it is</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td>

<td> •</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>You</td><td></td><td></td><td></td>

<td>&lt;u</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>you</td><td></td><td></td><td></td>

<td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ε</td><td></td><td>you</td><td></td>

<td></td><td></td><td></td><td>ΓΊ</td><td></td><td></td><td></td><td>rs</td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td>rs</td><td>M</td><td></td><td>Cs</td><td></td>

<td> 0</td><td></td><td></td><td>X</td><td></td><td></td><td></td><td>X</td><td></td><td></td><td></td><td></td><td>X</td><td></td><td></td><td></td><td></td><td>X</td><td></td><td></td><td></td><td>X</td><td></td><td></td><td></td><td>X</td><td> 0</td><td></td><td>X |</td><td></td>

<td>M</td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td>Qi</td><td></td><td></td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td>I heard</td><td></td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td>CM</td><td>«M</td><td>to</td><td></td><td></td>

<td>Ai</td><td></td><td></td><td>H</td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td>H</td><td></td><td>Φ</td><td> □</td><td></td>

<td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 4</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>M</td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>CQ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>rS</td><td>CO</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>CS</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td></td><td>rS</td><td></td><td>\or</td><td></td><td></td><td></td><td></td><td></td><td>tn</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>P</td><td></td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td>H</td><td>it is</td><td></td><td></td><td></td>

<td></td><td>Ό</td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>W</td><td></td><td></td><td></td><td></td><td>U</td><td></td><td>it is</td><td></td><td>CM</td><td></td><td></td><td></td><td> +</td><td> 2</td><td></td><td></td><td></td>

<td></td><td>• H</td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td> 2</td><td></td><td>H</td><td></td><td></td><td></td><td>and;</td><td>0i</td><td></td><td></td><td></td>

<td></td><td>OR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td> +</td><td></td><td>CM</td><td></td><td> +</td><td></td><td></td><td></td><td>z</td><td>H</td><td></td><td></td><td></td>

<td>you</td><td>you</td><td></td><td>z</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>z</td><td></td><td></td><td></td><td></td><td>Z</td><td></td><td>H</td><td></td><td>Z</td><td></td><td></td><td></td><td> 3</td><td> 4</td><td></td><td></td><td></td>

<td> '0</td><td>N</td><td>x_ »</td><td>W</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td>SAW</td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td>Cm</td><td>you*</td><td></td><td></td><td></td>

<td>• p |</td><td>• H</td><td>h</td><td>OR</td><td>you*</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td> +</td><td></td><td>or</td><td></td><td></td><td></td><td> 4</td><td>VO</td><td></td><td></td><td></td>

<td> □</td><td>you</td><td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td></td><td></td><td> «</td><td></td><td></td><td></td><td></td><td></td><td>CO</td><td>it is</td><td></td><td></td><td></td>

<td>you</td><td>you</td><td>H</td><td>r&gt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td>or</td><td></td><td>it is</td><td></td><td>or</td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td></td>

<td>h</td><td> 0)</td><td>you</td><td>Z</td><td>it is</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>z</td><td>you*</td><td></td><td></td><td></td><td>Z</td><td></td><td>(M</td><td></td><td>z</td><td></td><td></td><td></td><td>you*</td><td>H</td><td></td><td></td><td></td>

<td> 01</td><td>or</td><td>p.m</td><td>J</td><td> &gt;:</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 3</td><td></td><td></td><td></td><td></td><td> □</td><td> +</td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td>

<td>• d</td><td>OR</td><td>you</td><td>Cu</td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>Cm</td><td>x</td><td></td><td></td><td></td><td>Cm</td><td>it is</td><td>CM</td><td></td><td>Cm</td><td></td><td></td><td></td><td>or</td><td>z</td><td></td><td></td><td></td>

<td>¡G</td><td></td><td>υ</td><td></td><td>AND-*</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td></td><td> 2</td><td>CM</td><td></td><td></td><td></td><td></td><td></td><td></td><td>ω</td><td></td><td></td><td></td>

<td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td></td>

<td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> &lt;</td><td></td><td></td><td></td><td></td>

<td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>pS</td><td></td><td></td><td></td><td></td>

<td>you</td><td></td><td></td><td>co</td><td></td><td></td><td></td><td> 1*1</td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td></td>

<td>CM</td><td></td><td></td><td>-s.</td><td></td><td></td><td></td><td> \</td><td></td><td></td><td></td><td></td><td> \</td><td></td><td></td><td></td><td></td><td>«S.</td><td></td><td></td><td></td><td> \</td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td></td>

<td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td>

<td>you</td><td></td><td></td><td>you·</td><td></td><td></td><td></td><td>you*</td><td></td><td></td><td></td><td></td><td>you"</td><td></td><td></td><td></td><td></td><td>you*</td><td></td><td></td><td></td><td>you*</td><td></td><td></td><td></td><td> 4</td><td></td><td></td><td></td><td></td>

<td>I heard</td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td>CM</td><td></td><td></td><td></td><td>pS</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>I heard</td><td></td><td></td><td></td><td>I heard</td><td></td><td></td><td></td><td></td><td>I heard</td><td></td><td></td><td></td><td></td><td>I heard</td><td></td><td></td><td></td><td>I heard</td><td></td><td></td><td></td><td>Γ **</td><td>co</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>EM</td><td></td><td></td><td></td><td>Cm</td><td></td><td></td><td></td><td></td><td>Cm</td><td></td><td></td><td></td><td></td><td>Cm</td><td></td><td></td><td></td><td>Im</td><td></td><td></td><td></td><td>ro</td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>W</td><td></td><td></td><td></td><td>W</td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td>X »</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td>pH</td><td>you*</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> +</td><td>CM</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td> &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>&lt;C</td><td></td><td></td><td></td><td> 55</td><td>I heard</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>P</td><td></td><td></td><td></td><td></td><td>rS</td><td></td><td></td><td></td><td></td><td>pS</td><td></td><td></td><td></td><td>pS</td><td></td><td></td><td></td><td>Π</td><td>lx &lt;</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td>J</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>• -I</td><td></td><td></td><td></td><td></td><td>J</td><td></td><td></td><td></td><td>J</td><td></td><td></td><td></td><td>CU</td><td>in</td><td></td><td></td><td></td>

<td></td><td> 9</td><td></td><td>OR</td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td> 4</td><td> 4</td><td></td><td></td><td></td>

<td></td><td>B</td><td></td><td>CJ</td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td>to</td><td></td><td></td><td></td><td>r-1</td><td>σ&gt;</td><td></td><td></td><td></td>

<td></td><td> 0</td><td></td><td> +</td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td><td>oo</td><td>u&gt;</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>z</td><td></td><td></td><td></td><td></td><td>z</td><td></td><td></td><td></td><td></td><td>z</td><td></td><td></td><td></td><td>z</td><td></td><td></td><td></td><td>in</td><td>you*</td><td></td><td></td><td></td>

<td> 2</td><td>•OR</td><td></td><td>OR</td><td></td><td></td><td></td><td>n</td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>OR</td><td>to</td><td></td><td>cu</td><td></td><td></td><td></td><td>cu</td><td></td><td></td><td></td><td></td><td>m</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>cu</td><td></td><td></td><td></td><td>pS</td><td>or</td><td></td><td></td><td></td>

<td>H</td><td>W</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> +</td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td>pH</td><td></td><td></td><td></td><td>CS</td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td></td><td>you*</td><td></td><td></td><td></td><td>tn</td><td></td><td></td><td></td><td>U&gt;</td><td></td><td></td><td></td><td></td>

<td> -5</td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td>it is</td><td></td><td></td><td></td><td></td>

<td> 0</td><td>M</td><td></td><td>in</td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td>in</td><td></td><td></td><td></td><td></td>

<td>s</td><td>X</td><td></td><td>I heard</td><td></td><td></td><td></td><td>i heard</td><td></td><td></td><td></td><td></td><td>i heard</td><td></td><td></td><td></td><td></td><td>i heard</td><td></td><td></td><td></td><td>i heard</td><td></td><td></td><td></td><td>i heard</td><td></td><td></td><td></td><td></td>

tn tn r4 £

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M I heard σι χ «ι-i faith 2 Η * * C0 ιη ιο σι δ SS faith * ιη &lt;ν m ιη m

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> &lt;</td><td></td><td></td><td> &lt;*&gt;</td><td></td><td> +</td><td>Η</td><td></td>

<td></td><td></td><td></td><td></td><td></td><td>faith</td><td></td><td>ιη</td><td></td><td></td><td> «-1</td><td> +</td><td>Η</td><td>&lt;Ί</td><td></td>

<td></td><td></td><td></td><td> 04</td><td></td><td>Ο</td><td></td><td>Q</td><td></td><td></td><td> 2</td><td> 04</td><td>faith</td><td> *&lt;</td><td></td>

<td>ο</td><td>faith</td><td></td><td></td><td></td><td>Ν</td><td></td><td>Κ</td><td></td><td></td><td></td><td>faith</td><td>ϋ</td><td>ιη</td><td></td>

<td>ΰ</td><td> *</td><td></td><td>J</td><td></td><td> &gt;4</td><td> +</td><td>W</td><td></td><td></td><td>faith</td><td>d</td><td>Ν</td><td>Α</td><td></td>

<td> ©</td><td>r *</td><td></td><td> 2</td><td></td><td> *</td><td></td><td> *</td><td>Λ</td><td></td><td> ♦</td><td>faith</td><td> *&lt;</td><td>κ</td><td></td>

<td>σι</td><td>ιο</td><td></td><td> +</td><td></td><td>Ό</td><td> 04</td><td>rt</td><td> 10</td><td></td><td>φ</td><td> *</td><td> *</td><td>ω</td><td></td>

<td> 0 *-*</td><td>C4</td><td></td><td> 00</td><td></td><td> 04</td><td>ιη</td><td>ιη</td><td>φ</td><td> 04</td><td>η</td><td>σι</td><td> 04</td><td>ο ·</td><td>Λ</td>

<td>Μ ι ©</td><td></td><td></td><td>ιη</td><td></td><td> 04</td><td>ω</td><td>ΟΊ</td><td>Μ</td><td>ιη</td><td>ιο</td><td>θ '</td><td>Φ</td><td>σι</td><td> (0</td>

<td>* σ w</td><td></td><td> +</td><td>γ * 1</td><td> +</td><td></td><td></td><td></td><td>Λ</td><td>m</td><td></td><td>ο</td><td>Ό</td><td>σι</td><td>Φ</td>

<td>ri η &lt;</td><td></td><td>ο</td><td></td><td></td><td>Ο</td><td>ο</td><td>ο</td><td>Η</td><td></td><td>ο</td><td> +</td><td></td><td></td><td>Μ</td>

<td></td><td></td><td>m</td><td> 04</td><td> 04</td><td></td><td></td><td></td><td> 04</td><td>ο</td><td>II</td><td>U «Η</td><td>Ο</td><td>ο</td><td>X</td>

<td></td><td></td><td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> «</td><td></td><td>Tj</td><td></td><td> .</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ή</td><td></td><td>σι</td><td></td><td>rl</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>g</td><td></td><td> (0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 04</td><td> 5</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td> «</td><td> 0</td><td></td><td>ρ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Η</td><td>faith</td><td>&lt;Η</td><td> £</td><td>β</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>faith</td><td>Η</td><td></td><td>Φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> *</td><td> +</td><td></td><td>ο</td><td></td><td>V)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td> 04</td><td>I — 1</td><td> 00</td><td> *</td><td></td><td>V)</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>ι-4</td><td>η</td><td>Ό</td><td></td><td></td><td> *</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>ιη</td><td> '-,</td><td>m</td><td>ο</td><td></td><td> «»</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td>χ—</td><td></td><td>ιη</td><td></td><td>σι</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>ΰ</td><td> +</td><td> 2</td><td></td><td>ο</td><td></td>

<td></td><td> '0</td><td>Ο</td><td>faith</td><td> 04</td><td> +</td><td>ο</td>

<td></td><td>-Η</td><td>S</td><td>Η</td><td> 2</td><td>υ</td><td> +</td>

<td></td><td>ϋ</td><td>J</td><td> *</td><td>Η</td><td> 53</td><td> 04</td>

<td> £</td><td> ©</td><td>faith</td><td>Φ</td><td>W</td><td> 3</td><td> 2</td>

<td>Ό</td><td>Ν ~</td><td> *</td><td> &lt;0</td><td>Ο</td><td>faith</td><td>faith</td>

<td>• Η</td><td>Ή Μ</td><td>σι</td><td> 04</td><td>• κ</td><td> *</td><td>l · ·</td>

§5

Μ 01 ¡3 OI h Η Ή Ο Φ S ~ υ ιη η φ

Μ i »

<td></td><td></td><td></td><td> +</td><td></td>

<td>γ-4</td><td>«Φ</td><td></td><td>i-4</td><td></td>

<td> +</td><td>faith</td><td> +</td><td></td><td>Φ</td>

<td>Π</td><td>faith</td><td> %</td><td>rt</td><td>faith</td>

<td>Ο</td><td>faith</td><td>W</td><td>J</td><td>faith</td>

<td> 03</td><td>w</td><td>faith</td><td>or</td><td>faith</td>

<td> *</td><td> *</td><td> *</td><td>or</td><td>in</td>

<td>τ * 4</td><td>σι</td><td> &gt;</td><td> *</td><td> *</td>

<td> ®</td><td>Ό</td><td>OI</td><td>t</td><td>IO</td>

<td>ιη</td><td>Φ</td><td>ιη</td><td>in</td><td>in</td>

<td></td><td></td><td></td><td>φ</td><td>rt</td>

<td>γ-I</td><td>or</td><td>or</td><td></td><td></td>

<td></td><td> +</td><td>II</td><td>or</td><td>OR</td>

<td colspan="5"></td>

'Ü s «ιη ο

γ-1 ιη rH

Table 5A shows the relationship of standardized possibilities of each of the RS models using the data from the original Gene ID study described in Example 1 for the time to cR and for increase and reclassification in the combination of significant increase and reclassification. Table 5B shows the performance of each of the RS models that use the data from the complementary study CC (Cohorts 2 and 3) for augmentation and reclassification and the combination of significant increase and reclassification. In this context, amento refers to an increase in Gleason grade of 3 + 3 or 3 + 4 in biopsy greater than or equal to 3 + 4 in radical prostatectomy. Significant increase in this context refers to the increase in the degree of Gleason 3 + 3 or 3 + 4 in the biopsy equal to or greater than 4 + 3 in radical prostatectomy.

In addition, the gene groups used in the RS25 model were evaluated alone and in various combinations. Table 6A shows the results of this analysis using the data from the Gene Identification study and Table 6B shows the results of this analysis using the data from Cohorts 2 and 3 of the complementary study CC.

Gene expression for some genes can be

100 form at threshold, for example SRD5A2 Thresh = 5.5 if SRD5A2 &lt;5.5 or SRD5A2 if SRD5A2&gt; 5.5 and TPX2 Thresh = 5.0 if TPX2 &lt;5.0 or TPX2 if TPX2&gt; 5.0, where the gene symbols represent normalized gene expression values.

Non-scaled RS records derived from Table 4 can also be scaled back to be between 0 and 100. For example, RS27 can be scaled back to be between 0 and 100 as follows:

RS (scale) = 0 if 13.4 x (RSu + 10.5) &lt;0; 13.4 x (RSu + 10.5) if 0 &lt;13.4x (RSu + 10.5) &lt;100; or 100 if 13.4 x (RSu + 10.5)&gt; 100.

Using scaled RS, patients can be classified into low, high intermediate RS groups that use the prespecified cut-off points defined below in Table B. These cut-off points define the boundaries between low and intermediate RS groups and between groups. Intermediate and high RS. The cut-off points were derived from the discovery study with the intention of identifying substantial proportions of patients who on average had a clinically significant low or high risk of aggressive disease. In scaled RS it is rounded to the nearest integer before the cut-off points that define the RS groups are applied.

101

TABLE Β

<td>RS Group</td><td>Risk Registry</td>

<td>Low</td><td>Less than 16</td>

<td>Intermediate</td><td>Greater than or equal to 16 and less than 30</td>

<td>High</td><td>Greater than or equal to 30</td>

102

<img file="MX366164B_D0018.tif" />

Increase or Reclassification

Increase Significant Increase Reclassification Significant td ^ r-tndkooorco ^ o ^ dod ^ oooookodrddrdco

Udoioioioodkp ^ • rdkor-dM * ^ * ^ * coddOkD \ DOiokD in oo ci d r- dr-ooco ^ potnoioaoddkcokoinoo 4PO1OOODOOCO01Q ooioodddcidoit-kDiDoor-oi ιη .................. ... . .

Olrdrdrdrdrdrdd dHdddddddpdddddddd

<td>Pi 0</td><td>"-one 01 d</td><td>00 kO Cl</td><td>Γ- kD Cl</td><td>01 w M</td><td>m kO Cl</td><td>Γ- ΟΟ Cl</td><td>rd rd d</td><td>i — 1 OR d</td><td>kO co Cl</td><td>OI 0 d</td><td>- «r rd d</td><td>d d</td><td>d in d</td><td>0 Lf) d</td><td>d in d</td><td>in Cl d</td><td>01 d</td><td>co * M ·</td><td>0 d</td><td>OR Cl</td><td>00 r- V *</td><td>d 01</td><td>i heard d 'Φ</td><td>01 r- Τί &lt;</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>H</td><td> 00</td><td>d</td><td>kD</td><td>OR</td><td>Cl</td><td>in</td><td>rd</td><td> 01</td><td>cu</td><td>OI</td><td></td><td>in</td><td>kD</td><td>d</td><td> 00</td><td>I heard</td><td>d</td><td> 00</td><td>t-</td><td>d</td><td>in</td><td> «3·</td><td>r-</td><td>'φ</td>

<td>or</td><td> 00</td><td> 00</td><td> 00</td><td>ao</td><td> 00</td><td>rd</td><td>i heard</td><td>ao</td><td> 01</td><td>Γ-</td><td> 01</td><td> 0</td><td>OR</td><td>rd</td><td> 0</td><td> 01</td><td> 00</td><td>d</td><td>d</td><td>d</td><td>Cl</td><td>i heard</td><td>d</td><td>d</td>

<td>to)</td><td>Π</td><td>Cl</td><td>Cl</td><td>d</td><td>Cl</td><td>d</td><td>Cl</td><td>Cl</td><td>N</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>Cl</td><td>d</td><td> &lt;3*</td><td></td><td> «3*</td><td></td><td>d</td><td></td><td> &lt;3*</td>

<td>•or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>P.S</td><td> 0</td><td>Cl</td><td>CO</td><td> 0</td><td> 01</td><td> 00</td><td>I-</td><td> 01</td><td>d</td><td> 01</td><td></td><td>in</td><td>in</td><td>in</td><td>pH</td><td>P.S</td><td>d</td><td>pH</td><td>ID</td><td> 00</td><td>kO</td><td>kO</td><td>in</td>

<td>cffi</td><td></td><td></td><td></td><td>d</td><td></td><td>in</td><td> *·</td><td> &lt;3·</td><td> **</td><td> «3*</td><td></td><td>in</td><td>in</td><td>in</td><td>in</td><td>in</td><td></td><td> 01</td><td> 01</td><td> 01</td><td> 01</td><td>r-</td><td>OI</td><td> 00</td>

<td>m</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>σ \</td><td>i-1</td><td> 1—1</td><td> 1—1</td><td>t — 1</td><td>I — 1</td><td> 1—(</td><td>rd</td><td>l — 1</td><td>rd</td><td>r — 1</td><td> «—1</td><td>r — 1</td><td>rd</td><td>I — 1</td><td>r * 1</td><td> 1—1</td><td> 1—1</td><td> 1—1</td><td>i — l</td><td>l — l</td><td>i-1</td><td>r — 1</td><td>rd</td><td>CD</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>rd</td><td>OI</td><td>Cl</td><td>kp</td><td> 01</td><td></td><td>P-</td><td>kD</td><td>OI</td><td>σι</td><td>OI</td><td>r-</td><td>c-</td><td> 0</td><td> 00</td><td>d</td><td> 01</td><td>pH</td><td> 01</td><td>ao</td><td> 0</td><td>d</td><td>OR</td><td>OR</td>

<td>OR</td><td>OR</td><td> 01</td><td> 0</td><td>I heard</td><td> 01</td><td>Cl</td><td> 0</td><td> 0</td><td> 0</td><td> 01</td><td> 0</td><td>rd</td><td>rd</td><td>d</td><td>H</td><td>P ^</td><td> 01</td><td>I heard</td><td> 00</td><td>co</td><td>I heard</td><td>kO</td><td>OI</td><td> 00</td>

<td>OR</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Cl</td><td>rd</td><td>d</td><td>rd</td><td>rd</td><td>Cl</td><td>d</td><td>d</td><td>Cl</td><td> 1—1</td><td>d</td><td>d</td><td>d</td><td>Cl</td><td>d</td><td>d</td><td>P.S</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>1 — i</td><td>OI</td><td> 00</td><td> 01</td><td> 00</td><td>in</td><td> 1—1</td><td>ao</td><td>kD</td><td> 0</td><td> 0</td><td>r-</td><td>d</td><td>d</td><td>rd</td><td>r-</td><td> 00</td><td>d</td><td>ΙΛ</td><td>ao</td><td>in</td><td>Cl</td><td> 0</td><td>ao</td><td></td>

<td>OR</td><td></td><td></td><td></td><td></td><td></td><td> 00</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Cl</td><td> 0</td><td> 0</td><td>OR</td><td> 0</td><td></td><td>t-</td><td>kD</td><td> ^3*</td><td>ao</td><td>t-</td><td>r-</td><td>ao</td><td>kO</td><td>kO</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>Ifl</td><td>kO</td><td>d</td><td>d</td>

<td>&lt;u</td><td>rd</td><td>rd</td><td>r1</td><td>rd</td><td>t — 1</td><td> 00</td><td>rd</td><td>rd</td><td>rd</td><td>T — 1</td><td> «—&lt;</td><td>rd</td><td>rd</td><td>rd</td><td>pH</td><td>p4</td><td>i — l</td><td>r — I</td><td>ii</td><td> 1—1</td><td>P.S</td><td>rd</td><td>P.S</td><td>P.S</td>

<td> *0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>r-</td><td>OR</td><td>ao</td><td>kD</td><td> 00</td><td>kD</td><td>d</td><td>Ifl</td><td>Cl</td><td>kD</td><td> 01</td><td> 00</td><td>d</td><td>OR</td><td>in</td><td>k0</td><td>d</td><td> 00</td><td>Γ-</td><td>OR</td><td>LT</td><td>Γ-</td><td></td><td> «3&lt;</td>

<td> «#&gt;</td><td>m</td><td>d</td><td>t — 1</td><td>kO</td><td></td><td>in</td><td>co</td><td>d</td><td> 0</td><td> 0</td><td>r-</td><td> 1—1</td><td> 01</td><td>ifl</td><td>kO</td><td>in</td><td>r — 1</td><td>H</td><td> 00</td><td>OO</td><td>kfi</td><td>ao</td><td></td><td>Cl</td>

<td>in</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>σι</td><td></td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>in</td><td>in</td><td></td><td>in</td><td>in</td><td>U1</td><td>in</td><td>m</td><td>m</td><td></td><td></td><td></td><td>d</td><td>d</td><td>rr</td><td> *3·</td><td></td><td> &lt;3*</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>rd</td><td>co</td><td> 01</td><td> 0</td><td>kD</td><td> 0</td><td>kO</td><td> &lt;3*</td><td> 01</td><td>kO</td><td>d</td><td>kO</td><td>rd</td><td> 0</td><td>H</td><td>d</td><td>OR</td><td>Cl</td><td></td><td> 0</td><td>P.S</td><td>d</td><td>Γ-</td><td>kD</td>

<td>tote</td><td>m</td><td> 01</td><td> 00</td><td>d</td><td>OR</td><td>kD</td><td></td><td>m</td><td></td><td>in</td><td></td><td></td><td></td><td></td><td>r-</td><td>σι</td><td>pH</td><td>U1</td><td> 0</td><td>i heard</td><td> «·</td><td>co</td><td>in</td><td> &lt;3·</td>

<td>OR</td><td>r-</td><td>in</td><td>in</td><td>kD</td><td>kD</td><td>in</td><td> 0 1—1</td><td> 01</td><td>r-</td><td> 01</td><td>0 rd</td><td> 01</td><td>OR 1—1</td><td>OI</td><td> 01</td><td>r-</td><td>Γ-</td><td>Γ-</td><td>Γ-</td><td>kO</td><td> 00</td><td>co</td><td>c-</td><td>Γ-</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>M</td><td> «—1</td><td> 00</td><td>co</td><td>in</td><td>d</td><td>Cl</td><td> &lt;3*</td><td>rd</td><td>tn</td><td>OI</td><td>in</td><td>in</td><td> ^3·</td><td>m</td><td>i heard</td><td>ao</td><td>d</td><td> [-</td><td> 00</td><td>d</td><td>d</td><td>d</td><td>a</td><td>lf)</td>

<td>or</td><td>«J ·</td><td></td><td> &lt;3*</td><td></td><td></td><td>Φ</td><td>r-</td><td>Γ-</td><td>in</td><td>ao</td><td>c-</td><td> 0</td><td>OR</td><td> 0</td><td> 01</td><td>Γ-</td><td>ΙΛ</td><td>d</td><td> 0</td><td>pH</td><td> &lt;3&lt;</td><td>Ifl</td><td>P.S</td><td>d</td>

<td>fl)</td><td>Cl</td><td>Cl</td><td>d</td><td>Cl</td><td>Cl</td><td>Cl</td><td>d</td><td>d</td><td>Cl</td><td>Cl</td><td>Cl</td><td>d</td><td>d</td><td>d</td><td>Cl</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td>

<td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>Cl</td><td>rd</td><td> 01</td><td> 0</td><td>co</td><td>rd</td><td>r-</td><td></td><td>P *</td><td> 01</td><td>t-</td><td>d</td><td>in</td><td> *3·</td><td>d</td><td>d</td><td>d</td><td>d</td><td>kO</td><td>kO</td><td> 1/1</td><td> 01</td><td> 00</td><td>d</td>

<td>o \ o</td><td>Cl</td><td>Cl</td><td>H</td><td>Cl</td><td>rd</td><td>Cl</td><td>d</td><td>d</td><td>Cl</td><td>d</td><td>d</td><td></td><td>You*</td><td></td><td></td><td>d</td><td>d</td><td> 1/1</td><td> *3*</td><td> &lt;3·</td><td>Ifl</td><td>in</td><td></td><td>lf)</td>

<td>in</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 01</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>P.S</td><td>P.S</td><td>rd</td><td>rd</td><td>rd</td><td>P.S</td><td>rd</td><td>pH</td><td>pH</td><td>iH</td><td>pH</td><td>pH</td><td>P.S</td><td>P.S</td><td>P.S</td><td>P.S</td><td>P.S</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

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108

EXAMPLE 3: SELECTED GROUP ANALYSIS - STACKED FOR

IDENTIFY THE CO-EXPRESSED GENES

The purpose of the method of select-stacked groups of genes described in this example was to find a set of co-expressed biomarkers (or substitutes) that can be used to reliably predict the outcome as well as improve the genes described in the foregoing. The method used to identify coexpressed markers is illustrated in Figure 4. The set of co-expressed biomarkers was obtained by sowing the enumeration of maximum select groups (MCE) with cured biomarkers extracted from the scientific literature. The maximum select group enumeration method (MCE) [Bron et al., 1973] adds genes in the closely co-expressed groups such that all genes in the group have a similar expression profile. When all the genes in a group satisfy a condition of minimum similarity, the group is called a select group. When a select group is as large as possible without admitting any of the dissimilar genes in the select group, then the group is said to be maximum. Using the MCE method, all maximum selected groups are searched within a data set, the use of this method, almost any degree of overlap between the maximum selected groups can be found, as long as the overlap is supported by

109

<img file="MX366164B_D0024.tif" />

ss the data. The maximum selected group enumeration has shown [Borate et al., 2009] that it is an effective way to identify co-expressed gene modules (CGMs).

one. Definitions

The following table defines some commonly used terms in the analysis of select-stacked groups of genes.

Table 7

<td>Finished</td><td>Definition</td>

<td>Node</td><td>The abundance of a gene (for the purposes of CGM analysis)</td>

<td>Edge</td><td>A line that connects two nodes, indicating the co-expression of the two nodes</td>

<td>Graph</td><td>A collection of nodes and borders</td>

<td>Select Group</td><td>A graph with a border that connects all combinations in pairs of the nodes in the graph</td>

<td>Maximum select group</td><td>A select group that is not contained in any other group select</td>

<td>Piled up</td><td>A graph obtained by merging at least two groups select or stacked such that the overlap between the two select or stacked groups exceeds some user threshold definite</td>

<td>Expression profile</td><td>A two-dimensional matrix, with genes listed below the</td>

<td>gene</td><td>rows and samples listed through the columns. Each entry (i, j) in the matrix corresponds to the abundance of mRNA for the gene i and the sample j.</td>

two. Examples of selected and stacked groups

Figures 5A-5C show a family of three different graphs. A graph consists of nodes (numbered) and connection edges (lines). Figure 5A is not a group 25

110 selected because there are no edges that connect nodes 3 and 4. Figure 5B is a select group because there is an edge that connects all combinations in pairs of the nodes in the graph. Figure 5C is a select group, but not a maximum select group because it is contained in a select group (b). Given a graph with the connection edges, the MCE algorithm systematically triggers all the maximum selected groups with 3 or more nodes. For example, the graph in Figure 6 has two maximum select groups: 12-3-4-5 and 1-2-3-4-6.

When based on gene expression data, there are typically large numbers of maximum select groups that are very similar to each other. These maximum groups can be merged into stacks of selected maximum groups. Stacks are the final gene modules of interest and are generally much less the number that are the maximum select groups. Figure 7 schematically illustrates the stacking of two maximum select groups.

3. Sowing

For the purposes of finding substitute coexpressed markers, biomarkers in the literature can be identified and then used to sow MCE and stacking algorithms. The basic idea is as follows: for each seed, calculate a set of maximum selected groups (using the parallel MCE algorithm). Then stack

111 The maximum selected groups obtained from each seed, produce a set of seeded stacks. Finally, the stacking of the sown stacks to obtain a stacked sown stacked. Stacking of seeded stacks is an approximation to the stacks that would be obtained by using conventional MCE / stacking (i.e. not seeded) algorithms. The method used to identify the genes that are co-expressed with the genes described in the foregoing are described in Figure 4 and are described in more detail below.

3.1 MCE Sown Algorithm (steps 1-4)

one. The process begins by identifying an appropriate set, S_s, of planting genes. In the present case the planting genes were selected from the subsets of genes described in the above.

two. With the specified planting genes, select a correlation measurement, R (gi, g2), between the gene expression profiles of either of the two genes, gi, g₂, together with a correlation threshold below which gi, g₂, can be considered uncorrelated. For each sowing gene s in the sowing set S_s, find all

<td>gene pairs</td><td>(s, g)</td><td>in the data set such that</td><td>R (s, g)</td>

<td>is greater than or</td><td>same</td><td>to the correlation threshold. Leave</td><td>that G_s</td>

<td>be the union</td><td>of s</td><td>and the set of all</td><td>genes</td>

<td>correlated</td><td>with</td><td colspan="2">s. For the present study, the</td>

112 Spearman coefficient was used as the correlation measurement and 0.7 as the correlation threshold.

3. Calculate the correlation coefficient for each combination in pairs of genes (gi, gj) in G_s. Let X_s is the set of all gene pairs whereby R (gi, gj) is greater than or equal to the correlation threshold. If the genes were plotted as in Figure 5, there could be a border (line) between each pair of genes in X_s.

Four. Run the MCE algorithm, as described by

Schmidt et al. (J. Parallel Distrib. Comput. 69 (2009) 417-428) in the X gene pairs_s for each planting gene.

3.2 Sown stacking algorithm (steps 5-6)

The purpose of stacking is to reduce the number of select groups to a manageable number of gene modules (stacked). Continuing with stages 5 and 6 of Figure 4:

5. For each planting gene, select groups from the largest to the smallest, that is, the largest number of nodes to the smallest number of nodes. Of the remaining select groups, find the select group with the largest overlap. If the overlap exceeds a specific user threshold T, merge the two selected groups to form the first stack. Reorder the selected groups and stack (s) from the largest to the smallest and repeat the overlap and fusion test. Repeat the process until

113 A new merger is no longer present.

6. Now you have a set of stacks for each planting gene. In the final stage, all sown stacks are combined in a set of stacks, σ. As the final calculation, all stacks in σ are stacked, just as in step 5. This stack of stacks is the set of gene modules used for the present study.

The genes that were shown to co-express with the genes identified by this method are shown in Tables 8-11. Stacking ID in the Tables is simply an index to number the stacks and Probe Weight refers to the weight of the probe, or the number of times a probe (gene) is presented in the stack.

114

Table

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<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

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<td>you</td><td></td><td>rd</td><td>OI</td><td>rd</td><td></td><td>rd</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>I heard</td><td></td><td> £</td><td></td><td>OR"</td><td></td>

<td>Φ</td><td>or</td><td> &lt;3</td><td>you</td><td>you</td><td>υ</td><td></td><td></td><td></td><td></td><td>OR</td><td></td><td></td><td></td><td>or</td><td>you</td><td>C)</td><td>you</td><td>you</td><td></td><td> 2</td><td>you</td><td> 04</td><td></td>

<td>h</td><td> £</td><td></td><td></td><td> &lt;*»</td><td></td><td>"to"</td><td> 5</td><td></td><td>rd</td><td>OI</td><td>in</td><td></td><td>you</td><td>I heard</td><td>ro</td><td>0i</td><td></td><td></td><td></td><td></td><td></td><td> £</td><td></td>

<td>β i P&gt;</td><td>you</td><td>OR</td><td> ¡4</td><td>or</td><td>you</td><td> «4</td><td>you</td><td>rd</td><td>CO</td><td> 04</td><td>CO</td><td> £</td><td>Jgj</td><td>you</td><td> 4</td><td>you</td><td> .4</td><td> ►4</td><td> £</td><td>ro</td><td>i4</td><td>0i</td><td></td>

<td>Φ 0 X</td><td> 04</td><td>OR</td><td>or</td><td>or</td><td> 04</td><td>OR</td><td>υ</td><td> £</td><td>w</td><td> 01</td><td> (0</td><td>OR</td><td> 3</td><td> 04</td><td>í)</td><td> 04</td><td>OR</td><td>n</td><td>CO</td><td>n</td><td>n</td><td>OR</td><td>m</td>

<td>OU Φ</td><td>co</td><td>or</td><td>or</td><td>or</td><td>CO</td><td>CJ</td><td> &gt;</td><td> 04</td><td> £</td><td> 2</td><td>oi</td><td> 3</td><td>d</td><td>CO</td><td>CJ</td><td>CO</td><td>OR</td><td>CJ</td><td> £</td><td> 04</td><td>CJ</td><td>H</td><td> 04</td>

<td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>of the the D</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>-H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ό Qi M &lt;&lt;</td><td>rd</td><td>i — 1</td><td>rd</td><td>I heard</td><td>rd</td><td>OI</td><td>OR)</td><td>I heard</td><td>&lt;o</td><td>ro</td><td>Γ0</td><td>co</td><td>ro</td><td>fO</td><td></td><td></td><td></td><td></td><td></td><td> &lt;3*</td><td></td><td></td><td></td>

<td>from bra</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>you 3</td><td> £</td><td> 5</td><td>s</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td>g</td><td>g</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td></td>

<td>Φ * d</td><td>OR</td><td rowspan="2">0 m</td><td>or</td><td>OR</td><td>co</td><td>co</td><td>OR</td><td>co</td><td>M</td><td> 0</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>ro</td><td>CO</td><td>CO</td><td>ro</td><td>ro</td><td> 3</td>

<td>Or to</td><td>you</td><td> 01</td><td>you</td><td>you</td><td>you</td><td>you</td><td>you</td><td>ω</td><td>w</td><td>you</td><td>CU</td><td> 01</td><td>you</td><td> 01</td><td> 01</td><td>CU</td><td>you</td><td> £</td><td>n</td><td> £</td><td> £</td><td> £</td>

<td>from gives</td><td>rd</td><td></td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td> 0-</td><td></td>

<td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>S weight</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>you</td><td>rd</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>rd</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>you</td><td> «</td><td></td><td></td><td></td><td></td><td></td><td>rd</td><td></td><td></td><td>rd</td><td> £</td><td></td><td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>rd</td><td></td><td></td>

<td>Φ</td><td>Cí</td><td rowspan="2"> 04</td><td></td><td></td><td></td><td></td><td> 4</td><td></td><td></td><td>"you</td><td> 2</td><td>ro</td><td>I heard</td><td></td><td>you</td><td></td><td></td><td>you</td><td></td><td>you</td><td>you</td><td></td><td>you</td>

<td>k</td><td>OR</td><td></td><td> 04</td><td>rd</td><td></td><td>rd</td><td>rd</td><td></td><td>rd</td><td> 04</td><td></td><td>OR</td><td> 04</td><td>co</td><td></td><td> 04</td><td>CO</td><td></td><td></td><td> &lt;0</td><td></td><td></td>

<td>Yes</td><td>υ</td><td> 0«</td><td></td><td> 0«</td><td> £</td><td></td><td> &gt;4</td><td> &gt;</td><td> £2</td><td> &gt;4</td><td>CO</td><td> 2</td><td> (1</td><td> 04</td><td></td><td>Yes</td><td> 04</td><td> «4</td><td>t</td><td> 4</td><td> 4</td><td> 2</td><td>t4</td>

<td>Φ 0 K</td><td>or</td><td> £</td><td> £</td><td> £</td><td> £</td><td> £</td><td>OR</td><td> £</td><td> £</td><td>OR</td><td>Ω</td><td> 5*</td><td> &gt;4</td><td> £</td><td>Π</td><td>h *</td><td> £</td><td>OR</td><td> £</td><td>OR</td><td>OR</td><td>you</td><td>OR</td>

<td>oo ®</td><td>co</td><td>OR</td><td>ω</td><td></td><td>E-&gt;</td><td>ω</td><td>OR</td><td>H</td><td> 3</td><td>OR</td><td> 04</td><td> 0«</td><td>CO</td><td> 4</td><td>CJ</td><td> **</td><td></td><td>CJ</td><td></td><td>CJ</td><td>CJ</td><td> £</td><td>OR</td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>of the the D</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>-id</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ό &amp; H «you</td><td>laughed</td><td>rd</td><td>rd</td><td>r »</td><td>I heard</td><td>I heard</td><td>ro</td><td>ro</td><td>ro</td><td></td><td> ·«·</td><td></td><td>in</td><td>ΙΛ</td><td>in</td><td></td><td>w</td><td>C0</td><td></td><td> 0-</td><td></td><td> €0</td><td> 00</td>

ιη o

ιΗ in rd

115

<td>Planting gene</td><td>THBS2</td><td>THBS2</td><td>THBS2</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>from gives</td><td>r — i</td><td>ι — 1</td><td> (—1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>to</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>S weight</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>• d</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>or</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Φ</td><td>I heard</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>h</td><td>in</td><td>ro</td><td>faith</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>C&gt; Qi</td><td>TO</td><td></td><td> ¡5</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Φ 0 X</td><td> 2</td><td>OR</td><td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>C¡&gt; O Φ</td><td>H</td><td>OR</td><td> &gt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Η Ό</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Φ Λ Ό iH</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>* 0 q, w</td><td>t— (</td><td>i — 1</td><td>r-1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>from ibra:</td><td>CJ</td><td>to</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>OR</td><td>OR</td><td>OR</td><td>(J</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td rowspan="2">OR 0</td><td>CJ</td>

<td>. H</td><td> 0</td><td>oi</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td>δ</td><td>δ</td><td>δ</td><td>δ</td><td></td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td>to 3</td><td></td><td></td><td> 3</td><td></td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> &lt;</td><td></td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td><td> 3</td>

<td>Φ * d</td><td>CU</td><td>CU</td><td>cu</td><td> 0&lt;</td><td>cu</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

<td>O &lt;n</td><td>co</td><td>co</td><td>co</td><td>co</td><td>co</td><td>CO</td><td>co</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>W</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td>

<td>from gives</td><td></td><td></td><td>ro</td><td>ro</td><td> 04</td><td> 04</td><td>OI</td><td>OI</td><td>OI</td><td>OJ</td><td>H</td><td>H</td><td>ι — 1</td><td>OR"</td><td>CO</td><td>in</td><td>in</td><td>in</td><td>in</td><td></td><td></td><td>co</td><td>ro</td><td>co</td><td>Γ0</td>

<td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>or «n Or you 0 ι — 1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>• β</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>you</td><td></td><td rowspan="2"> 01</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 04</td><td></td>

<td>to</td><td></td><td> 04</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 04</td><td> 04</td><td></td><td></td><td>σι</td><td></td><td> 04</td><td></td><td></td><td></td><td></td><td></td><td>»Q</td><td></td>

<td> ©</td><td>or</td><td>(I</td><td>h)</td><td></td><td></td><td>H</td><td>in</td><td> 04</td><td> 0</td><td>you*</td><td></td><td></td><td></td><td></td><td>Φ</td><td>co</td><td>rd</td><td></td><td> 0</td><td rowspan="2"> §</td><td></td><td>in</td><td></td><td></td><td>CJ</td>

<td>h</td><td> 0</td><td> 0</td><td>CO</td><td>i — 4</td><td>t-4</td><td>r-1</td><td>δ</td><td>rtj</td><td> 0</td><td></td><td>LD</td><td>M *</td><td></td><td></td><td></td><td> 04</td><td></td><td>co</td><td>rl *</td><td rowspan="2">0 TO</td><td> 2</td><td> 0</td><td></td><td></td>

<td>aunt</td><td> 3</td><td>Q</td><td> &gt;&lt;</td><td> 2</td><td>or</td><td>s</td><td> 3</td><td></td><td> 0</td><td> 2</td><td>CO</td><td>h-4</td><td>J</td><td> 2</td><td> 2</td><td> 0</td><td>w</td><td> &gt;4</td><td> 2</td><td> 3</td><td> 3</td><td> 0</td><td> 0</td><td rowspan="2">0 M</td>

<td>φ ox</td><td>cu</td><td>Q</td><td> 04</td><td> 0</td><td> 0</td><td> 3</td><td> 0</td><td></td><td>CO</td><td> 2</td><td>V)</td><td>OR</td><td>or</td><td> 0</td><td> 2</td><td>OR</td><td>Q</td><td> 0</td><td> 3</td><td> 0</td><td>h</td><td> 0</td><td>P- »</td><td> 0</td>

<td>OU 0</td><td>co</td><td>cu</td><td>to</td><td> 0</td><td> 0</td><td>to</td><td> 0</td><td></td><td>J-4</td><td></td><td> 0</td><td>or</td><td>or</td><td> 0</td><td></td><td>co</td><td>υ</td><td>Q</td><td></td><td>CO</td><td>CO</td><td> 0</td><td></td><td> 0</td><td> £</td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>h * d</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>φ you Ό ι — 1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>• H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Ό 0. H &lt;</td><td>in</td><td>in</td><td>m</td><td>ΙΛ</td><td>in</td><td>LT)</td><td>m</td><td>m</td><td>tfj</td><td>in</td><td>in</td><td>in</td><td>in</td><td>co</td><td>CO</td><td>co</td><td>co</td><td>co</td><td>co</td><td>co</td><td>CD</td><td>CO</td><td>CO</td><td>co</td><td>CO</td>

<td>from ra</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>rd</td><td>i — 4</td><td>i — 1</td><td>i — 4</td><td>r — i</td><td> «—4</td><td>f1</td><td>rt</td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>•to</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>C</td><td></td><td></td><td> &lt;</td><td> &lt;</td><td></td><td></td><td></td><td> &lt;</td><td>&lt;c</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 4</td>

<td>_s</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ro</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>co</td><td>co</td><td>co</td><td>co</td><td>co</td><td>CO</td><td>co</td><td>CO</td><td>co</td><td>co</td>

<td>ace</td><td> %</td><td> %</td><td> &amp;</td><td>s</td><td>δ</td><td>δ</td><td> 2</td><td>►q</td><td></td><td> 0</td><td> 4-4</td><td>►q</td><td> 0</td><td> 0</td><td></td><td>J</td><td>• J</td><td></td><td>&gt; q</td><td>&gt; q</td><td>►q</td><td></td><td>+ q</td><td>►q</td><td>t4</td>

<td>φ «H</td><td>C9</td><td>C * J</td><td>CO</td><td>or</td><td>or</td><td>or</td><td>OR</td><td>or</td><td>F)</td><td>or</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>OR</td><td>Π</td><td>OR</td><td>or</td><td>n</td><td>or</td><td>n</td><td>π</td><td>or</td><td>OR</td>

<td>Or to</td><td> 04</td><td> 04</td><td> 04</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td>or</td><td>OR</td><td>CJ</td><td>or</td><td>CJ</td><td>OR</td><td>or</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>or</td><td>CJ</td><td>or</td><td>or</td><td>OR</td><td>or</td>

<td>Φ * o</td><td></td><td>Mr</td><td>ro</td><td>ro</td><td>ro</td><td>co</td><td>rU</td><td>rU</td><td>j — 4</td><td>i — 4</td><td>ro</td><td>co</td><td> 04</td><td> 04</td><td>rd</td><td>rd</td><td>rd</td><td>co</td><td>co</td><td>ΓΟ</td><td>ro</td><td> 04</td><td>or"</td><td>rU</td><td>r- (</td>

<td>you</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>0 you Φ you 0 rH</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>ado</td><td></td><td></td><td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>to</td><td>H</td><td></td><td> 0</td><td></td><td></td><td> 0</td><td></td><td></td><td> 1—4</td><td></td><td> «-4</td><td></td><td></td><td></td><td></td><td></td><td></td><td> 04</td><td> 0</td><td> &gt;</td><td></td><td></td><td></td><td></td><td></td>

<td>φ</td><td>* aj</td><td>n</td><td> 04</td><td>OR</td><td></td><td> 3</td><td>OI</td><td>OI</td><td> *&lt;</td><td></td><td></td><td>CJ</td><td></td><td>d¡</td><td></td><td></td><td></td><td></td><td> 0</td><td> 0</td><td></td><td></td><td></td><td>rij</td><td>CJ</td>

<td>M</td><td>co</td><td></td><td>OR</td><td> 0</td><td rowspan="2">g</td><td> 0</td><td>co</td><td>CO</td><td>ro</td><td>faith</td><td>CO</td><td>δ</td><td></td><td>M *</td><td>faith</td><td></td><td></td><td></td><td> 0</td><td> 0</td><td></td><td></td><td> 0</td><td>CO</td><td> 0</td>

<td>a p &lt;</td><td></td><td>faith</td><td>or</td><td rowspan="2">i</td><td>OR</td><td> 0</td><td> 0</td><td></td><td> ¡5</td><td> 0</td><td> 3</td><td>H</td><td>OR</td><td> 2</td><td>OR</td><td> 2</td><td> &gt;4</td><td> £</td><td> 0</td><td> 2</td><td>w</td><td> 0</td><td></td><td> 3</td>

<td>Φ 0 X</td><td>OR</td><td rowspan="2"> £</td><td>ll</td><td> 2</td><td>Q</td><td>to</td><td>X</td><td>OR</td><td>CJ</td><td>OR</td><td> 0</td><td> 2</td><td>OR</td><td>tj</td><td>OR</td><td> 0</td><td>OR</td><td>n</td><td>OR</td><td> 0</td><td>n</td><td>W</td><td>or</td><td> 0</td>

<td>CJ U β</td><td>or</td><td>co</td><td>co</td><td>H</td><td> 0</td><td>H</td><td>H</td><td>or</td><td> !&gt;</td><td>υ</td><td>co</td><td> 0</td><td>or</td><td> &gt;</td><td>or</td><td> 0</td><td>CJ</td><td> 0</td><td> 4-4</td><td> 0</td><td>CJ</td><td></td><td>CJ</td><td>CO</td>

<td> 0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>f-1 Ό Φ you Ό H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>-rl</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>* 0 0 «H tíj</td><td> 00</td><td> 00</td><td>co</td><td> 00</td><td> 00</td><td> 00</td><td> 00</td><td>«H</td><td>H</td><td>H</td><td> 04</td><td> 04</td><td> 04</td><td>OI</td><td> 04</td><td> 04</td><td> 01</td><td>CO</td><td>CO</td><td>CO</td><td>CO</td><td>co</td><td>CO</td><td>co</td><td>co</td>

ιη o

rd

LO rd * »«

116

<td>Planting gene</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Probe weight</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>0 »D © to Φ s ¿| ou «J</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Stack Id</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Planting gene</td><td>SPARC</td><td>SPARC</td><td>SPARC</td><td>SPARC</td><td>to § faith ω</td><td></td><td></td><td></td><td></td>

<td>Probe weight</td><td> 04</td><td> 04</td><td>Rh</td><td>c4</td><td>H</td><td></td><td></td><td></td><td></td>

<td>Gen Co- expressed</td><td>rl</td><td>EDIL3</td><td>C0L3A1</td><td>IGFBP7</td><td>HEG1</td><td></td><td></td><td></td><td></td>

<td>Stack Id</td><td>Ό</td><td>Ό</td><td>vo</td><td> 10</td><td></td><td></td><td></td><td></td><td></td>

<td>Planting gene</td><td>COL3A1</td><td>H rt! m 8</td><td>C0L3A1</td><td>C0L3A1</td><td>COL3A1</td><td>COL3A1</td><td>COL3A1</td><td>COL3A1 1</td><td>COL3A1</td>

<td>Probe weight</td><td>THE</td><td>Φ</td><td></td><td>m</td><td> 04</td><td> 04</td><td>r-1</td><td>i—&lt;</td><td>r-t</td>

<td>Gen Co- expresado</td><td>C0L3A1</td><td>BGN</td><td>C0L1A1</td><td>SPARC</td><td>m</td><td>PDGFRB</td><td>C0L1A2</td><td>r4</td><td>THBS2</td>

<td>Id del Apilado</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td><td>Φ</td>

ιη ιη rH

117

Tabla

<td>Gen de siembra</td><td>SED5A2</td><td>SRD5A2</td><td>a LO</td><td>a</td><td>SRD5A2</td><td></td><td>a</td><td>a</td><td>a</td><td>a</td><td>SRD5A2</td><td>a to</td><td>a to</td><td>a É</td><td>a to</td><td>SED5A2</td><td>SRD5A2</td><td>SRD5A2</td><td>a É</td><td>a ω</td><td>SRD5A2</td><td>a É</td><td>a to</td>

<td>Peso de la sonda</td><td>Φ Ch ΙΛ H</td><td> 12616</td><td> 12395</td><td> 12218</td><td>to OI r-í OI r4</td><td> 11552</td><td> 11061</td><td> 10811</td><td> 10654</td><td> 10330</td><td>ττοοτ</td><td> 9588</td><td>to o m σ»</td><td>(•Ί o in σ</td><td> 9304</td><td> 8659</td><td> 8908</td><td> 7949</td><td>ZLLL</td><td> 7514</td><td> 7078</td><td> 6903</td><td> 6374</td>

<td>Gen Co- expresado</td><td>fe OI s</td><td></td><td>i</td><td> 1</td><td>§ en en</td><td>MKX</td><td>H</td><td>Φ un en in Φ to</td><td> 1</td><td>to</td><td>á</td><td>TSHZ3</td><td> !</td><td></td><td>CLO</td><td>_l</td><td> 1</td><td></td><td>ω</td><td>PCDH18</td><td>3 H</td><td>ΓΠΗ5</td><td>to</td>

<td>l^-1 *Q *8 i-i</td><td>ft</td><td>i-1</td><td>H</td><td>i—l</td><td>r4</td><td>H</td><td>H</td><td>r4</td><td>r-(</td><td>i—1</td><td>H</td><td>i—1</td><td>H</td><td>γΊ</td><td>rd</td><td>fH</td><td>H</td><td>cd</td><td>H</td><td>rH</td><td>H</td><td>i—1</td><td>i—4</td>

<td>Gen de siembra</td><td>o</td><td>i</td><td>i</td><td>i</td><td> 1</td><td>i</td><td></td><td>í</td><td> !</td><td>i</td><td>i</td><td>i</td><td></td><td></td><td>i</td><td> 1</td><td>i</td><td>GSTM2</td><td>i</td><td>Ü</td><td>i</td><td>i</td><td>i</td>

<td>Peso de la sonda</td><td> 168</td><td>m IO «—1</td><td> 162</td><td> 161</td><td> 158</td><td> 155</td><td> 154</td><td> 152</td><td> 147</td><td> 142</td><td>H Φ r4</td><td> 131</td><td> 130</td><td> 127</td><td> 125</td><td> 118</td><td> 101</td><td>OI o-</td><td> 99</td><td>o to</td><td>co LO</td><td>04 LO</td><td> 47</td>

<td>Gen Co-expresado</td><td>H H</td><td>TGEBR3</td><td>ω</td><td> 1</td><td>_i</td><td>H</td><td>B</td><td>i</td><td>_l</td><td></td><td>_?</td><td>Í</td><td>I</td><td>l</td><td>PPAP2B</td><td>i</td><td>n to Ψ4 S rH OI U</td><td>POPDC2</td><td>TPM2</td><td>CDC42EP3</td><td>CCDC69</td><td>CRISPLD2</td><td> 2 8</td>

<td>Id del Apilado</td><td>rd</td><td>rH</td><td>r4</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>cH</td><td>H</td><td>H</td><td>H</td><td>«H</td><td></td><td>H</td><td>H</td><td>rl</td><td>H</td><td>H</td><td>H</td><td>1“I</td><td>r4</td>

<td>Gen de i siembra ]</td><td>0* υ</td><td>Γ- υ</td><td>r- U</td><td>o· U</td><td>Ο- υ</td><td>O· u</td><td>ο- υ</td><td>Γ- Ü</td><td>O* u</td><td>ο- υ</td><td>0- U</td><td>Δ0</td><td>C7</td><td>r· U</td><td>ο- Ο</td><td>&gt; O</td><td>ο- υ</td><td>C7</td><td>C7</td><td>C7</td><td>C7</td><td>Ο- υ</td><td>&gt; C7</td>

<td>Weight of the probe</td><td> 26870</td><td> 25953 |</td><td> 24985</td><td>in 04 co Φ 04</td><td> 24327</td><td> 23197</td><td> 22847</td><td> 22236</td><td> 20623</td><td> 20345</td><td> 19461</td><td> 19280</td><td> 18689</td><td>Φ o ~ to or ri</td><td> 18367</td><td> 18355</td><td> 16871</td><td>OI to un to j - l</td><td> 14936</td><td> 14789</td><td> 14748</td><td> 13590</td><td> 13332</td>

<td>Gen Co-expressed</td><td> 1</td><td>SPARCL1</td><td>FAT4</td><td></td><td>SLC8A1</td><td>MEIS1</td><td>H</td><td></td><td>DPYSL3</td><td>r4 faith §</td><td>SGK269</td><td></td><td>gj</td><td></td><td>TGEBR3</td><td>rd</td><td>C1S</td><td>σι</td><td>PCDH18</td><td>c</td><td>PDGFC</td><td></td><td>g</td>

<td>Ό ph H H¹</td><td>H</td><td>r-1</td><td></td><td>r-1</td><td>i-1</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>Rh</td><td>Rh</td><td>H</td><td>r4</td><td>H</td><td>rd</td><td>H</td><td></td><td>Rh</td><td> 1</td><td>H</td><td></td><td>«H</td><td>Rh</td>

Or r4

Lf)

118

<img file="MX366164B_D0025.tif" />

<td>Sen of sowing</td><td>to AND</td><td>to Ul</td><td></td><td>É</td><td>i</td><td>a Ul</td><td>SRD5A2</td><td>a</td><td>a</td><td>a</td><td>a</td><td> 3</td><td>a ω</td><td>a ω</td><td>a</td><td>SRD5A2</td><td>a 0</td><td>a É</td><td>a 0</td><td>a É</td><td> 1</td><td>a 0</td><td>a 0</td><td>a 0</td><td>a 0</td>

<td>Peso de la sonda</td><td>en id Oí 10</td><td>00 O id 0</td><td>tí· σι tí·</td><td>σι co r- tí·</td><td>id Oí id tí·</td><td>id σι o tí·</td><td>C- id en n</td><td>(*l &lt;n co m</td><td>id 4» ω C)</td><td>Γ- ιο 00 (tí</td><td>00 o co Oí</td><td>tí· σι 10 Oí</td><td>rd O tí· OI</td><td>o σι Oí OI</td><td>in o OI OI</td><td>Oí 10 id OJ</td><td>10 σι σι rd</td><td>(*l co σι rd</td><td>m Γ— Γ- Η</td><td>H &lt;*l Γ- Η</td><td>ΙΛ rC 10 H</td><td>tí* 01 in H</td><td>&lt;*l o 0 H</td><td>H CO tí» H</td><td>o o re H</td>

<td>1 2 18 í</td><td> 1</td><td></td><td>id §</td><td> !</td><td> §</td><td></td><td> 1</td><td>g</td><td></td><td></td><td>l</td><td></td><td> £</td><td></td><td></td><td>£tí</td><td>id OI É¡</td><td>tí&lt; O σι CC ω</td><td> 0</td><td>i s</td><td> 0</td><td>g</td><td></td><td>i</td><td> 1</td>

<td> &lt;¡1 83</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>Gen de siembra</td><td> 1</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>OJ Ü</td><td>i</td><td>i</td><td>i</td><td> 1</td><td>I</td><td>i</td><td>i</td><td>i</td><td>Ü</td><td></td><td>i</td><td>H §</td><td>H §</td><td>H 04 Ü H</td><td>H 01 Ü H</td><td>H 04 8</td><td>H 04 o H</td>

<td>Peso de la sonda</td><td>tí· tí&lt;</td><td>O tí·</td><td>00 ro</td><td> 10</td><td>00 OI</td><td>10 OJ</td><td>o OJ</td><td>00 rd</td><td>r- id</td><td>id id</td><td>id id</td><td>σι</td><td>σι</td><td>t—</td><td>in</td><td>&lt;*l</td><td>Oí</td><td>OJ</td><td>H</td><td>H</td><td>H</td><td>H</td><td> 3</td><td>tí· H</td><td>tí· H</td>

<td>•i tt 2 $8</td><td></td><td> 1</td><td>h</td><td></td><td>H</td><td>tí* 04 3</td><td>U</td><td> 1</td><td>O id i</td><td>id 0</td><td> 1</td><td>o¡ to U</td><td>m W w a</td><td>tí; 8</td><td>h</td><td>H</td><td></td><td>¡3 c!</td><td>H e 8</td><td>g</td><td>a H</td><td> 1</td><td>g</td><td>2* s</td><td> «</td>

<td>Id del Apilado</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>rd</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>(tí</td><td>OJ</td><td>Oí</td>

<td>Gen de | siembra |</td><td>t— u</td><td>C- u</td><td>Γ— U</td><td>0* U</td><td>ο- Ο</td><td>Γ— u</td><td>ο- υ</td><td>Γ— u</td><td>Ο- υ</td><td>ο- υ</td><td>ο- υ</td><td>Γ- a</td><td>r- a</td><td>C— U</td><td>t— U</td><td>Γ- U</td><td>o</td><td>c</td><td>Γ- u</td><td>r- u</td><td>Γ- U</td><td>ο- υ</td><td>D</td><td>ο- υ</td><td>Γ- u</td>

<td>*8 ° *§ 01 c © tí 0 04 id a</td><td>Γ- o id 4*1 id</td><td>id 00 0 Oí id</td><td>in m &lt;*i oí id</td><td>m &lt;*&gt; id Oí d</td><td>ιη 0 σι rí id</td><td>tí· LO σι id id</td><td>00 co 00 id rd</td><td>tí· 00 f*l id rd</td><td>id OJ id id id</td><td>0 10 ir o id</td><td>o tí· OJ o id</td><td>oí |d rd O id</td><td>o o co σι</td><td>σι Γ- Oí σι</td><td>id m rd σι</td><td>Oí o tn 00</td><td>r- Γ* tí· co</td><td>in OJ tí· 00</td><td>co U&gt; σι r-</td><td>o CC 01 &lt;0</td><td>tí· OJ 00 10</td><td>H σι [-· «0</td><td>H H 10 •0</td><td>ID O tí· 0</td><td>σι H OJ 0</td>

<td>1 a 2 $3</td><td>I</td><td>Ϊ</td><td>a id W</td><td></td><td>H</td><td>s !</td><td> 1</td><td>í</td><td>m 1 04</td><td> §</td><td></td><td></td><td>H</td><td>i</td><td> 0</td><td>rn</td><td></td><td>H</td><td> 1</td><td></td><td>i</td><td></td><td>_f</td><td>£ a</td><td></td>

<td>Id del Apilado</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>rd</td><td>id</td><td>id</td><td>rd</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>id</td><td>rd</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td>

ιη o

rH ιη

119

<td>« &lt;0 d 0 W</td><td>SRD5A2</td><td>Si ut</td><td>l</td><td>a ω</td><td>§ LO</td><td> §</td><td>a ut</td><td>SRD5A2</td><td>SED5A2</td><td>a ^t</td><td>a</td><td>SRD5A2</td><td>SRD5A2</td><td>SRD5A2</td><td>SKD5A2</td><td>a É</td><td>a ut</td><td>a in</td><td>SED5A2</td><td>SKD5A2</td><td>SRD5A2</td><td>SRD5A2</td><td>a É</td><td>a</td><td>a l£t</td>

<td>Peso de la sonda</td><td>^f r- π «rt</td><td>04 o o» rt</td><td>rt en rrt «rt</td><td>o en «rt «rt</td><td>r- o «rt rt</td><td>p- CO σ&gt;</td><td>o rt Ot</td><td>rt &lt;n p-</td><td>Ut r- p-</td><td>rt rt</td><td>rt Ο- ΚΟ</td><td>00 kO kO</td><td>rt rt kD</td><td>Ot rt ut</td><td>Ut o Ut</td><td>rt Ot</td><td>o o- &lt;F</td><td>00 OI ’F</td><td>O ot rt</td><td>rt 00 n</td><td>04 04 rt</td><td>F rt rt</td><td>co r- 01</td><td>Ot rt 01</td><td>en en «rt</td>

<td>Gen Co- expresado</td><td>ω</td><td>8 g 0</td><td>O g)</td><td>i</td><td> §</td><td>λ</td><td>kO co rt M-t kd 0</td><td>APHGAP10</td><td>CU a</td><td>Ot ω</td><td>a Oí a w</td><td>n ω</td><td>rt a H</td><td> 0</td><td> 1</td><td>rt</td><td>g</td><td>rt</td><td></td><td>rt kO &lt;rt &amp; rt 01 U</td><td>CRISPLD2</td><td>i</td><td>ο- υ</td><td>i</td><td></td>

<td>Id del Apilado</td><td>i—1</td><td>rt</td><td>«rt</td><td>rrt</td><td>rt</td><td>i—I</td><td>rt</td><td>rrt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td>

<td>Gen de 1 siembra ||</td><td>«rt Cu 0 H</td><td>rt fe 8</td><td>«rt fe 0 K</td><td>«rt δ H</td><td>«rt Cu 0 H</td><td>rt Cu 8</td><td>Cu 8</td><td>fe 8</td><td>rt fe 0 rt</td><td>a 8</td><td>rt δ rt</td><td>rt Cu 8</td><td>fe 8</td><td>fí 0 H</td><td>rt §</td><td>rt fe 0 H</td><td>rt fe 8</td><td>rt δ H</td><td>rt Cu 0 H</td><td>fe 8</td><td>rt fe 0 H</td><td>fe 8</td><td>fe 8</td><td>£ 0 H</td><td>rt fe 0 H</td>

<td>Peso de la sonda</td><td>rt «-1</td><td>rt rrt</td><td>OI «rt</td><td>0t</td><td>ot</td><td> 00</td><td>CO</td><td>P-</td><td>P-</td><td>KO</td><td>ut</td><td>rt*</td><td>sF</td><td> *·</td><td>&lt;F</td><td>*F</td><td>«F</td><td></td><td>TF</td><td>*F</td><td>sF</td><td>F</td><td>F</td><td>F</td><td>F</td>

<td>Gen Co-expresado</td><td></td><td>_l</td><td>fe 8</td><td>&lt;n «rt i</td><td>en ω</td><td>KATNAL1</td><td>rt rt &lt;44 rt 0</td><td>3 kO «rt a w</td><td>g</td><td></td><td>ut ut «4 8 rt 0</td><td>Clorfl74</td><td>_l</td><td>kO 1 2</td><td>js</td><td></td><td>rt N e</td><td>i M</td><td></td><td>en OI OI 44 S rt 0</td><td> 1</td><td>g</td><td> !</td><td>¡rt</td><td>rt rt</td>

<td>Id del Apilado</td><td>n</td><td> 01</td><td>n</td><td> 01</td><td> 01</td><td> 04</td><td>OI</td><td>OI</td><td> 01</td><td>OI</td><td>Oí</td><td> 04</td><td>OI</td><td> 01</td><td> 01</td><td>OI</td><td> 04</td><td> 01</td><td> 01</td><td> 01</td><td>OI</td><td>OI</td><td> 01</td><td>OI</td><td>OI</td>

<td>Gen de I siembra </td><td>ο- υ</td><td>r- 0</td><td>r- 0</td><td>r- 0</td><td>P- 0</td><td>p- 0</td><td>p- 0</td><td>p- 0</td><td>r~ 0</td><td>o- 0</td><td>p- 0</td><td>p- 0</td><td>p- 0</td><td>p- 0</td><td>P- 0</td><td>P- 0</td><td>O- 0</td><td>P- 0</td><td>t- 0</td><td>O- 0</td><td> 0- 0</td><td> 0- 0</td><td> 0- 0</td><td>ο- υ</td><td>Ο- υ</td>

<td>Peso de la sonda</td><td>«rt ut «rt kO</td><td>Γ- Ot CO ut</td><td>04 rt&lt; CO ut</td><td>04 O CO Ut</td><td>rt CO 0* Ut</td><td>rt O rt ut</td><td>rt K0 o ut</td><td>00 OI 00 &lt;F</td><td>ut OI co -F</td><td>kO P- *F</td><td>«0 rt* rt*</td><td>en OI rt ’F</td><td>p- ut OI *F</td><td>00 ot Γ- ΓΟ</td><td>Ot P- kD rt</td><td>oo Ο- ΚΟ rt</td><td>rt Ο- ΚΟ rt</td><td>co rt -F rt</td><td>OI ^F rt rt</td><td>kO OI rt n</td><td>rt KO ot OI</td><td>ut OI Ot OI</td><td>rt F P- 01</td><td>ot o ko 04</td><td>en rt Ut OI</td>

<td>1 w Φ J</td><td>s</td><td>s £</td><td>rrt W</td><td></td><td></td><td> 1</td><td>C0L14A1</td><td>rt</td><td></td><td>H</td><td></td><td>B</td><td>I</td><td> 1</td><td> § §</td><td></td><td>g</td><td> 1</td><td>g w w</td><td>rt</td><td>a i</td><td>KO F F 04 rt</td><td></td><td>04 OJ</td><td>rt</td>

<td>H § •3 Λ s's·</td><td>«rt</td><td>irt</td><td> 1 **</td><td>«rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>«rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td> 1</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td>

LO

LD rH

120

<td>Sen de siembra</td><td>SRD5A2</td><td>SRD5A2</td><td>a tn</td><td>a ω</td><td></td><td>SRD5A2</td><td>SRD5A2</td><td>SKD5A2</td><td>SHD5A2</td><td>a</td><td>a É</td><td>SRD5A2</td><td>a É</td><td>SRD5A2</td><td>SRD5A2</td><td>SRD5A2</td><td>SKD5A2</td><td>SRD5A2</td><td>SRD5A2</td><td>a É</td><td>SRD5A2</td><td>SRD5A2</td><td>a Λ</td><td>a ω</td><td>SRD5A2</td>

<td>Peso de la sonda</td><td> 174</td><td> 173</td><td> 168</td><td>u&gt; kO rd</td><td>¹⁶⁵</td><td> 123</td><td> 100</td><td> 01 01</td><td>O 01</td><td>Oí co</td><td>o o·</td><td>rq k0</td><td>01 in</td><td>rd un</td><td>CO rq</td><td>tn rq</td><td>0- Oí</td><td>rd Oí</td><td>tn rd</td><td> 00</td><td></td><td> 01</td><td> 01</td><td>Ol</td><td>rd</td>

<td>Gen Co- expresado</td><td></td><td></td><td>fe</td><td>GPR124</td><td>01 01 o- Ol tn ω</td><td></td><td></td><td>i</td><td>H</td><td>i</td><td> 5</td><td></td><td> 1</td><td>MAML2</td><td>i</td><td> £1</td><td>UST</td><td>1MLHE</td><td>H</td><td>C5orf4</td><td>GSTM5P1</td><td>É υ</td><td>CM</td><td> 0</td><td> 0</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>id</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>Gen de I siembra J</td><td>rd fe §</td><td>rd §</td><td>rd 1% O H</td><td>rd §</td><td>IGFl</td><td>IGFl</td><td>rd &amp; H</td><td>rd fe Ü H</td><td>rd δ H</td><td>fe s</td><td>rd fe O H</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>rd fe Ü H</td><td>IGFl</td><td>IGFl</td><td>fe a</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>rd §</td><td>rd fe Ü H</td>

<td>Peso de la sonda</td><td></td><td></td><td></td><td></td><td></td><td>«a*</td><td> &lt;3*</td><td></td><td> &lt;3*</td><td> &lt;3·</td><td></td><td></td><td>M·</td><td></td><td> *1·</td><td></td><td> &lt;3*</td><td> &lt;3&lt;</td><td> &lt;3*</td><td></td><td> «3*</td><td></td><td></td><td></td><td></td>

<td>1 o s J</td><td>DSCR3</td><td>SLC35F1</td><td>C22orf25</td><td></td><td>a ui fe M fe</td><td>SUPT7L</td><td>C10orf78</td><td></td><td>ClorflSl</td><td>í? fe Oí a £</td><td>SEC62</td><td>_l</td><td>01 Ol kO Λ</td><td>m un</td><td>H</td><td></td><td></td><td>KIAA1737</td><td>APOBEC3F</td><td></td><td>SIKEl</td><td>HSP90B3P</td><td>l</td><td>Ol rd 03 Md b rd υ</td><td>ZNF70</td>

<td>H -8 •8 3 S 2</td><td>oí</td><td>Oí</td><td>Oí</td><td>Oí</td><td>O!</td><td>OJ</td><td> 01</td><td>OJ</td><td>Oí</td><td> 01</td><td> 01</td><td>Oí</td><td>Oí</td><td>Oí</td><td> 01</td><td>Oí</td><td> 01</td><td>OI</td><td> 01</td><td> 01</td><td>(S</td><td> 01</td><td> 01</td><td> 03</td><td>Ol</td>

<td>Gen de J siembra ,</td><td>r- υ</td><td>&gt; U</td><td>υ</td><td>f» υ</td><td> 1*</td><td>C7 J</td><td>ο- υ</td><td>ο- υ</td><td>ο- υ</td><td>C7</td><td>ο- υ</td><td>ο- υ</td><td>ο- υ</td><td>ο- υ</td><td>ο- υ</td><td>C7</td><td>C7</td><td>ο- υ</td><td>C7</td><td>C7</td><td>C7</td><td>C7</td><td>C7</td><td>C7</td><td>G</td>

<td>Peso de la sonda</td><td> 2353</td><td> 2278</td><td> 2115</td><td>kO σι σι rd</td><td> 1980</td><td> 1939</td><td> 1748</td><td>kfi ω kf&gt; rd</td><td>-ψ 01 tn rd</td><td> 1503</td><td> 1470</td><td> 1464</td><td> 1433</td><td> 1224</td><td> 1181</td><td> 1168</td><td> 1029</td><td>cq Ol 01</td><td> 970</td><td> 942</td><td> 889</td><td>01 Lfi co</td><td>m kO</td><td> 708</td><td>Ol 01 kO</td>

<td>1 a 2 &amp; la</td><td></td><td>w</td><td>i</td><td>CHRDL1</td><td>i</td><td>EFEMP1</td><td></td><td></td><td>w</td><td> 2·</td><td>01 01 0» ÍS un y</td><td>PREX2</td><td> ¡</td><td>rd</td><td></td><td>£ Si</td><td>a</td><td>01 kO g Ü</td><td>3 fe</td><td>IL33</td><td>CCDC80</td><td> §</td><td>SEC23A</td><td> §</td><td>m</td>

<td></td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td></td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

LD

O rH in

H

<img file="MX366164B_D0026.tif" />

121

<td>Gen de siembra</td><td>t—1 H rd g 8</td><td>rd H i—1 g 8</td><td>rd H i”d g 8</td><td>rd H rd g 8</td><td>rd H rd g 8</td><td>rd H rd g 8</td><td>rd H rd g 8</td><td>rd H id</td><td>rd H</td><td>rd H rd g 8</td><td>rd H rd g 8</td><td>rd H rd g 8</td><td>rd H</td><td>rd H rd g 8</td><td>rd t-d rd g 8</td><td>rd H rd g 8</td><td>rd H rd g 8</td><td>rd H rd g 8</td><td>rd H r^|</td><td>rd H</td><td>rd t-d rd g 8</td><td>rd H g 8</td><td>rd H rd g 8</td><td>TGFB1I1</td><td>TGFB1I1</td>

<td>Peso de la sonda</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>00 rd</td><td>tn rd</td><td>rd rd</td><td>rd rd</td><td>O rd</td><td>O rd</td><td>O rd</td><td> 00</td><td> 00</td><td>r&gt;</td><td>US</td><td>es</td><td>m</td><td>CD</td><td>CD</td><td>CD</td>

<td>Ί §</td><td>SO «r oo 00 CD r-</td><td>Ai 3</td><td>í</td><td>£1 fe a</td><td></td><td></td><td></td><td></td><td></td><td>S</td><td>rd H rd g 8</td><td> 1</td><td>&lt;T&gt; fe §</td><td></td><td>g</td><td> 1</td><td>fe</td><td></td><td>s B</td><td>i</td><td></td><td> 1</td><td>rd</td><td>CD H</td><td>SO 00 tn o os 3</td>

<td>Id del Apilado</td><td>t-d</td><td>rd</td><td>rd</td><td>CD</td><td>CD</td><td>CD</td><td>m</td><td>m</td><td>m</td><td></td><td>«Φ</td><td></td><td>•Φ</td><td> -3«</td><td>M·</td><td>xF</td><td></td><td>•D·</td><td>'¡r</td><td>M·</td><td></td><td>-D·</td><td></td><td>D·</td><td>^í*</td>

<td>8 1 81 O Q</td><td>i-( fe O H</td><td>rd fe o H</td><td>rd fe O H</td><td>fe 8</td><td>rd fe O H</td><td>rd fe 8</td><td>rd fe O H</td><td>rd fe 8</td><td>rd fe o H</td><td> £ 8</td><td>rd fe O H</td><td>rd fe Ü H</td><td>rd fe 8</td><td>a 8</td><td>rd fe O H</td><td>rd fe O H</td><td>E¡ 8</td><td>rd s H</td><td>E¡ 8</td><td>rd B H</td><td>rd fe 8</td><td>rd</td><td>rd fe 8</td><td>rd</td><td>rd fe 8 H</td>

<td>Peso de la sonda</td><td></td><td>•Φ</td><td></td><td></td><td></td><td></td><td>M·</td><td></td><td></td><td></td><td>F</td><td>*F</td><td>^F</td><td></td><td></td><td> &lt;4»</td><td> «4·</td><td></td><td></td><td>^P</td><td></td><td></td><td></td><td>•Φ</td><td></td>

<td>í n 8 3 1¿</td><td>&gt; CD H</td><td>r·1 9</td><td>£&gt; fe § a</td><td>SO</td><td></td><td>r- rd M-l a rd rd u</td><td>en σι rd OS CD</td><td>rd</td><td>rd</td><td>^O</td><td>00 rd Ud U O 0</td><td>$D fe H</td><td></td><td>*&lt; CD</td><td>O Γ- &gt; en 5p</td><td>CD O us OS CD rd O O H</td><td></td><td>_f</td><td>i</td><td>CD a tn CD</td><td></td><td>en rd tn O</td><td>00 rd fe W</td><td></td><td>O OS i</td>

<td>1-1*8 «3 sa·</td><td>Oí</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td>

<td>Ί si O n</td><td>r- U</td><td>r- U</td><td>Γ- υ</td><td>t U</td><td>Γ* U</td><td>u</td><td>P- ü</td><td>r- υ</td><td>r* υ</td><td>r- U</td><td>P- U</td><td>r- U</td><td>t-» U</td><td>&gt; u</td><td>c</td><td>G</td><td>U</td><td>U</td><td>Γ* u</td><td>Γ* U</td><td>r* u</td><td>C&gt; U</td><td>r* u</td><td>r* υ</td><td>&gt; u</td>

<td>Peso de la sonda</td><td>00 O SO</td><td>σι 00 in</td><td>so SO tn</td><td>σι ΙΌ ιη</td><td>d· CD tn</td><td>rd CD</td><td>&gt; rd «r</td><td>so r- «Ό</td><td>CD CD en</td><td>en rd en</td><td>rd O PS</td><td>rd σι CD</td><td>CD r· CD</td><td>tn Ό· CD</td><td>tn CD</td><td>OS so rd</td><td>SO so rd</td><td>CD rd rd</td><td>o rd rd</td><td>O so</td><td>so m</td><td>CD rd</td><td>CD rd</td><td></td><td>rd</td>

<td>1 O 8 J</td><td>iH</td><td></td><td>00 tn 4d 8 r- U</td><td>&lt;Ό fe fe CD i</td><td></td><td>§ B</td><td>w</td><td>i</td><td></td><td>CD fe</td><td></td><td>W</td><td>w</td><td>a</td><td></td><td>i</td><td>6) SO •4 t-d</td><td> !</td><td>rd »3</td><td>H</td><td>a g</td><td>i 8 fe</td><td>rd i</td><td>i</td><td>&amp; g 8</td>

<td> 83</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td> 1</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

LO rd

<img file="MX366164B_D0027.tif" />

122

<td>Gen de siembra</td><td>TGFB1I1</td><td>rd H r^</td><td>TGFB1I1</td><td>rd H rd e B</td><td>rd H rd e B</td><td>TGFB1I1 1_</td><td>TGFB1I1</td><td>TGFB1I1</td><td>rd H rd g B</td><td>rd H rd g B</td><td>TGFB1I1</td><td>rd H rd g B</td><td>TGFB1I1</td><td>TGFB1I1</td><td>rd H rd g B</td><td>TGFB1I1</td><td>rd H rd g B</td><td>rd H rd g B</td><td>TGFB1I1</td><td>IGFB1I1</td><td>rd H rd g B</td><td>TGFB1I1</td><td>TGFB1I1</td><td>rd H rd g B</td><td>TGFB1I1</td>

<td>Peso de la sonda</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td> 381</td><td> 362</td><td> 321</td><td> 317</td><td> 306</td><td>d σι d</td><td> 287</td><td> 275</td><td> 253</td><td> 222</td><td>LO rd d</td><td>rd d</td><td> 206</td><td> 184</td><td> 163</td><td> 163</td><td>(A Φ rd</td><td> 157</td><td> 140</td><td>&lt;a &lt;A rd</td>

<td>(0 s $8 1</td><td></td><td>LA</td><td></td><td>ID «· CO 00 d</td><td>SLC24A3</td><td> 1</td><td>FDLIM7</td><td>A0C3</td><td>^A</td><td></td><td>a * d</td><td></td><td></td><td>TGFB1I1</td><td></td><td>DES</td><td> 1</td><td></td><td></td><td>RASL12</td><td>LO %</td><td>KCNMBl</td><td> 1</td><td>GPR124</td><td>C0L6A1</td>

<td>Id del Apilado</td><td></td><td></td><td>«J*</td><td></td><td></td><td>la</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td>

<td>Gen de siembra</td><td>rd fe Ü H</td><td>fe s</td><td>rd δ H</td><td>fe 8</td><td>fe 8</td><td>rd fe Ü H</td><td>fe 8</td><td>IGF1</td><td>IGFl</td><td>rd fe H</td><td>rd</td><td>fe 8</td><td>IGFl</td><td>rd fe O H</td><td>rd §</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>rd fe 8</td><td>fe 8</td>

<td>Peso de la sonda</td><td>-d·</td><td></td><td></td><td>•a·</td><td></td><td> *3*</td><td></td><td> *·</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>’J’</td><td></td><td></td><td> 5*</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Gen Co-expresado</td><td>EDE12</td><td>C10orf76</td><td>d</td><td>RRN3P1</td><td>LOC100127925</td><td>SC4M0L</td><td>AP4E1</td><td>AP0LD1</td><td> 1</td><td> 10</td><td>ι %</td><td></td><td>PARD6B</td><td>STOM</td><td>CYP20A1</td><td></td><td>ATP1B4</td><td>lo</td><td>CEP170L .</td><td></td><td>m</td><td></td><td>0SBPL2</td><td>H</td><td>d g</td>

<td>SS¹</td><td>d</td><td>d</td><td>Oí</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td>

<td>Gen de siembra</td><td></td><td>ω fe §</td><td>$ s</td><td>W g</td><td>g</td><td>ω g</td><td></td><td>DES</td><td></td><td>ω g</td><td></td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>W g</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>a</td><td>DES</td>

<td>Peso de la sonda</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td> 72309</td><td> 72305</td><td> 72049</td><td> 69837</td><td> 68389</td><td> 67725</td><td> 67225</td><td> 66488</td><td> 65707</td><td>rd 0&gt; d LA LO</td><td> 65217</td><td> 65097</td><td>00 d * LO</td>

<td>1 n Φ 1 $8</td><td>S0RBS1</td><td>u</td><td>DES</td><td>ΓΠΗ5</td><td></td><td>ATP1A2</td><td>ITIH5</td><td>DES</td><td></td><td></td><td>DES</td><td>H</td><td></td><td> 1</td><td>TNS1</td><td>CNN1</td><td> 1</td><td>CHRDL1</td><td>DFYSL3</td><td> 0</td><td>VCL</td><td></td><td>SLC8A1</td><td>MEIS1</td><td>ATP2B4</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>d</td><td> 01</td><td>d</td><td>ro</td><td></td><td>f*1</td><td> *·</td><td></td><td></td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>LA</td><td>IA</td><td>LA</td><td>IA</td>

ιη ο

γΗ ιη

123

<td>Gen de siembra</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGEB1I1</td><td>rd H rd E 8</td><td>rd H rd e 8</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TCFB1I1</td><td>TGFB1I1</td><td>rd H rd e 8</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGEB1I1</td><td>TGFB1I1</td><td>rd H rd e 8</td><td>TGFB1I1</td><td>TGFB1I1</td><td>rd H rd E 8</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGFB1I1</td><td>rd H rd E 8</td>

<td>Peso de la sonda</td><td> 127</td><td> 124</td><td> 121</td><td> 121</td><td>d rd rd</td><td> 111</td><td> 108</td><td>εοτ</td><td> 102</td><td>o os</td><td>rd CO</td><td>rd CO</td><td>co r-</td><td>US r-</td><td>CO so</td><td>ro so</td><td>ro so</td><td>co us</td><td>co US</td><td>SO US</td><td>so</td><td>ro</td><td>rd -Φ</td><td>os rs</td><td>co ro</td>

<td>1 tt s 1</td><td></td><td>COL6A2</td><td></td><td>H</td><td>TNS1</td><td>i</td><td>HSEB8</td><td>co I s</td><td>MYH11</td><td>GEFT 1-</td><td></td><td></td><td>i</td><td>MRVIl</td><td></td><td></td><td>RBPMS2</td><td></td><td>d</td><td>rd i</td><td>H</td><td>H</td><td>d i</td><td>MRC2</td><td>HRNBP3</td>

<td>Id del Apilado</td><td>us</td><td>un</td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td><td>us</td><td>us</td><td>US</td><td>US</td><td>US</td><td>us</td><td>US</td><td>US</td><td>us</td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td><td>us</td>

<td>Gen de siembra</td><td>rd S H</td><td>rd fe Ü H</td><td>rd fe a</td><td>fe 8</td><td>rd fe 8</td><td>rd fe O H</td><td>IGF1</td><td>rd fe C9 H</td><td>IGFl</td><td>IGFl</td><td>rd fe 8</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>rd fe O H</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>rd fe Ü H</td><td>rd fe Ü H</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>fe 8</td>

<td>Peso de la sonda</td><td></td><td></td><td></td><td> *3*</td><td></td><td></td><td> &lt;3*</td><td>«Φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> *3·</td><td> &lt;3·</td><td> &lt;3»</td><td>M·</td><td></td><td>’i’</td>

<td>Gen Co-expresado</td><td>ZNF772</td><td>ro r* os so &lt;3·</td><td>so os o 00 d rd O o H</td><td>H</td><td>Θ s</td><td>DISC2</td><td>CYCS</td><td>d W N</td><td>L0C646127</td><td>KRP15</td><td>Γ- US rs o ro rd o o rd</td><td>rd CO E</td><td>i</td><td>J0SD1</td><td>s</td><td>LIN54</td><td>d 3 OS d</td><td>_l</td><td>H6PD</td><td>FBXW2</td><td>ro</td><td></td><td>ANGEL2</td><td>i</td><td>MAPK1IP1L</td>

<td>si</td><td>d</td><td>d</td><td>Oí</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td>

<td>Gen de j siembra 1</td><td>W B</td><td> 1</td><td>w §</td><td>DES |</td><td>ω B</td><td>DES |</td><td>w B</td><td>W B</td><td>co §</td><td>C0 B</td><td></td><td> 1</td><td>DES</td><td>DES</td><td>co B</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td></td><td>DES</td><td>DES</td>

<td>Peso de la sonda</td><td> 64293</td><td> 64271</td><td> 63359</td><td> 61499</td><td> 60803</td><td>r- *5· OS OS US</td><td> 59840</td><td> 58329</td><td> 58303</td><td> 56889</td><td> 56620</td><td> 56591 1</td><td> 54990</td><td> 54713</td><td> 53979</td><td> 53386</td><td> 53378</td><td> 52082</td><td> 51556</td><td> 51205</td><td>US rd so Os</td><td> 49292</td><td> 48293</td><td> 46190</td><td>so d os &lt;3·</td>

<td>i Φ 1 Se</td><td>DDR2</td><td>IM0D1</td><td>S0RBS1</td><td></td><td></td><td>co s</td><td></td><td>_i</td><td>r^</td><td>r- Θ fe</td><td></td><td>i</td><td>DES</td><td>i</td><td>CO SO os d y</td><td></td><td>d fe US</td><td>rd W</td><td>d</td><td></td><td>CAVI</td><td></td><td>rs</td><td></td><td>rd i</td>

<td>d S 2</td><td>LC</td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td><td>us</td><td>US</td><td>US</td><td>us</td><td>US</td><td>US</td><td>US</td><td>us</td><td>US</td><td>US</td><td></td><td>US</td><td>US</td><td>US</td><td>US</td><td>US</td>

LT)

O i—I

124

<td>Gen de siembra</td><td>IGFB1I1</td><td>TGFB1I1</td><td>i—1 H rl g 8</td><td>© © © E 8</td><td>TGFB1I1</td><td>TGFB1I1</td><td>¡ TGFB1I1 1-</td><td>TGFB1I1</td><td>TGFB1I1</td><td>© © © g 8</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGFB1I1</td><td>© H © e 8</td><td>TGFB1I1</td><td>TCFBIII</td><td>© H © e 8</td><td>© H © e 8</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGFB1I1</td><td> © © ©</td><td>TGFB1I1</td>

<td>Peso de la sonda</td><td>kD ©</td><td>Lf) d</td><td>Cl Cl</td><td>o Cl</td><td> 19</td><td>oo ©</td><td>co ©</td><td>c» ©</td><td> &gt; ©</td><td>TT ©</td><td>Cl ©</td><td>Cl ©</td><td> © ©</td><td> © ©</td><td> © ©</td><td>o ©</td><td>oo</td><td>Γ*</td><td>kD</td><td>kO</td><td>lf)</td><td>tí·</td><td>Tí·</td><td> ©</td><td>Cl</td>

<td>1 01 Φ Sel</td><td>d</td><td>CLIP3</td><td>C16or£45</td><td>d</td><td> 3</td><td>RAERES2</td><td>ADRA1A</td><td>TINAGL1</td><td>i</td><td></td><td>C0PZ2</td><td>LTBP4</td><td>l</td><td>© fe</td><td>PCDH10</td><td>RAB34</td><td> © !</td><td>TCF7L1</td><td></td><td> ©</td><td>ZNF516</td><td>i</td><td> ©</td><td>fe</td><td>SYDE1</td>

<td>Id del Apilado</td><td>m</td><td>in</td><td>lf)</td><td>in</td><td>in</td><td>in</td><td>Lf)</td><td>in</td><td>Lf)</td><td>lf)</td><td>Ifl</td><td>in</td><td>lf)</td><td>Lf)</td><td>lf)</td><td>lf)</td><td>lf)</td><td>lf)</td><td>lf)</td><td>lf)</td><td>lf)</td><td>lf)</td><td>in</td><td> ©</td><td>Lf)</td>

<td>Gen de siembra</td><td>IGFl</td><td>rl fe 8</td><td>© fe O H</td><td>© β</td><td>© δ H</td><td>© fe Ü H</td><td> © §</td><td>© δ H</td><td>© fe 8</td><td>© δ H</td><td>IGFl</td><td>© fe O ©</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td>© &amp; H</td><td>IGFl</td><td>IGFl</td><td>IGFl</td><td> 5¡ 8</td><td>IGFl</td><td>© fe O H</td><td>© fe 8</td>

<td>Peso de la sonda</td><td></td><td>Tí·</td><td>Tí·</td><td>Tí·</td><td>Ό»</td><td></td><td>Tí·</td><td> *·</td><td>Tí·</td><td>Tí·</td><td></td><td>t*</td><td>TJ»</td><td>Tí·</td><td>Ό·</td><td>Tí·</td><td>ΤΓ</td><td>TI·</td><td>TT</td><td></td><td> &lt;3·</td><td>Tí·</td><td>tT</td><td>Tí·</td><td>Tf</td>

<td> 1 (0 8 £</td><td>σ\ ω N</td><td>FXC1</td><td> ©</td><td>M0BKL1A</td><td>kD ©</td><td>© kD U-l a kD ©</td><td> 1</td><td>i</td><td>OT</td><td>kD © Cl o © © o o © y</td><td>Cl TI· Tf o © © o o © y</td><td></td><td>ZBTB3</td><td>ZNF445</td><td>00 fe</td><td>RAB21</td><td>ZC3HAV1L</td><td>SC5DL</td><td>s</td><td></td><td>KCNE4</td><td>GM2A</td><td>LOC401588</td><td>O) f- «M tí CO u</td><td>KIAA0754</td>

<td>d s a</td><td>ci</td><td>d</td><td>Cl</td><td>d</td><td>d</td><td>Cl</td><td>Cl</td><td>Cl</td><td>Cl</td><td>Cl</td><td>Cl</td><td>Cl</td><td>Cl</td><td>Cl</td><td>d</td><td>d</td><td>Cl</td><td>d</td><td>d</td><td>d</td><td>Cl</td><td>d</td><td>d</td><td>d</td><td>Cl</td>

<td>Gen de 1 siembra ]</td><td>w g</td><td>W g</td><td>W g</td><td></td><td>ω g</td><td> 1</td><td>DES</td><td>w g</td><td>DES</td><td>DES</td><td>03 g</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>DES</td><td>ω g</td><td>DES</td><td>DES</td><td>DES</td><td>ω g</td><td>DES</td><td>DES</td><td>DES</td>

<td>Peso de la sonda</td><td> 44120</td><td>-Φ ci kD ©</td><td> 43602</td><td>in © c- Cl ©·</td><td> 42364</td><td> 41435</td><td> 37460</td><td> 33800</td><td> 33287</td><td> 32935</td><td> 32471</td><td> 32337</td><td> 29867</td><td> 29746</td><td> 28983</td><td> 28923</td><td> 28732</td><td>kD kD C* C· d</td><td> 27521</td><td> 27335</td><td> 25944</td><td>kD CO © in Cl</td><td> 25377</td><td> 25146</td><td> 24888</td>

<td> 1 &lt;0 3 58</td><td>j</td><td></td><td>SERPINF1</td><td> ©</td><td></td><td>HSPB8</td><td></td><td></td><td>TSPAN18</td><td></td><td> © 3</td><td></td><td></td><td>l</td><td>PPAP2B</td><td> © ©</td><td>O fe y</td><td>r$</td><td>i</td><td>kD Tí· Tí· Cl ©</td><td>MEIS2</td><td> ©</td><td></td><td></td><td>CLU</td>

<td>sa·</td><td>in</td><td>in</td><td>in</td><td>in</td><td>m</td><td>in</td><td>in</td><td>in</td><td>lf)</td><td>lf)</td><td>lf)</td><td>Lf)</td><td>Lf)</td><td>in</td><td>Lf)</td><td>lf)</td><td>lf)</td><td>lf)</td><td>Ifl</td><td>lf)</td><td>lf)</td><td>lf)</td><td>lf)</td><td>lf)</td><td>Lf)</td>

LO in i—I

125

<td>Gen de siembra</td><td>TGFB1I1</td><td>TGFB1I1</td><td>TGFB1I1</td><td>A H r—1 e</td><td>rd H A</td><td>rd H A</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>i</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td>

<td></td><td rowspan="2">C3</td><td rowspan="2">Oí</td><td></td><td></td><td></td><td></td><td> 00</td><td></td><td>un</td><td>σι</td><td>un</td><td> 00</td><td>Tt*</td><td>O</td><td>un</td><td>A</td><td>P</td><td>LO</td><td> 03</td><td> 00</td><td> 00</td><td>un</td><td>o</td><td> 3*</td><td> 3*</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td>σι</td><td></td><td>co</td><td>LO</td><td>LO</td><td> 3*</td><td>rd</td><td>LO</td><td>en</td><td>o</td><td>Γ3</td><td>O</td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 3*</td><td>P</td><td>un</td><td>Tt*</td><td></td><td>LO</td><td>en</td><td>o</td><td></td><td>CO</td><td>A</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 03</td><td></td><td></td><td></td><td></td><td>O</td><td>o</td><td>o</td><td> 01</td><td>σι</td><td>σι</td><td>σι</td><td>o\</td><td> 00</td><td>CO</td><td> 00</td>

<td>§ e</td><td></td><td></td><td></td><td></td><td></td><td></td><td>en</td><td>en</td><td>en</td><td>ei</td><td>en</td><td>en</td><td>en</td><td>en</td><td>en</td><td>en</td><td>en</td><td> 03</td><td> 03</td><td> 03</td><td> 03</td><td>OI</td><td> 03</td><td> 03</td><td> 03</td>

<td>Φ &lt;0 0 fe A W</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 8</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>CO Q</td><td>3· s</td><td></td><td></td><td>A</td><td></td><td>LO</td><td></td><td>Z</td><td></td><td></td><td>rd A</td><td>rd</td><td></td><td>&lt;N</td><td> 03</td><td>A</td><td>en</td><td>A</td><td>a</td><td></td><td></td><td rowspan="2"> §</td><td> 03</td><td>A</td><td></td>

<td></td><td>H</td><td></td><td></td><td></td><td></td><td>É9</td><td></td><td>Π</td><td></td><td></td><td></td><td></td><td></td><td>&lt;í</td><td></td><td></td><td></td><td></td><td>CQ</td><td rowspan="2">CQ g</td><td></td><td></td><td></td><td></td>

<td>$8 í</td><td>fe fe CU</td><td> 1</td><td>e</td><td>s</td><td></td><td>fe 8</td><td>s</td><td> %</td><td></td><td>o</td><td>É</td><td></td><td>i</td><td></td><td> §</td><td> 8</td><td></td><td>8 CQ</td><td></td><td> £</td><td></td><td>É</td><td>H</td><td>έ</td>

<td>rt 8</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 83</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>•rl</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>s a</td><td>in</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td>

<td>Φ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> •0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> &lt;0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> $</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>A</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>A</td><td>A</td><td>A</td><td rowspan="2"> £</td><td>A</td><td>rd</td><td>A</td><td>A</td><td>A</td>

<td></td><td></td><td></td><td></td><td></td><td>fe</td><td>fe</td><td>fe</td><td>fe</td><td></td><td></td><td>fe</td><td>fe</td><td></td><td></td><td></td><td>fe</td><td></td><td></td><td>fe</td><td>fe</td><td>fe</td><td>fe</td><td>fe</td><td>te</td>

<td></td><td>ñ</td><td>O</td><td>O</td><td>C9</td><td>ü</td><td>O</td><td>n</td><td>O</td><td>en</td><td>O</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> §</td><td> 0</td><td> 0</td><td> 0</td><td>P</td><td> 0</td><td>g</td><td> 2</td><td> 0</td>

<td>0 &lt;D</td><td>ñ</td><td> ¡=¡</td><td>H</td><td>H</td><td>H</td><td>H</td><td>A</td><td>H</td><td>H</td><td>A</td><td>A</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>A</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> &lt;0</td><td> 3*</td><td>tf</td><td> 3*</td><td> 3*</td><td> 3*</td><td> 3*</td><td> •3·</td><td> *3»</td><td> *3*</td><td> 3&lt;</td><td> 3»</td><td> 3·</td><td> 3*</td><td> 3·</td><td> 3»</td><td> 3*</td><td> 3*</td><td> 3*</td><td> 3*</td><td> 3*</td><td> 3*</td><td> 3*</td><td> 3*</td><td> 3*</td><td> 3</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>o *q</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>a 3</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>φ ω o cu *0 a</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>o</td><td></td><td></td><td></td><td>P</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td>σι</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> (0</td><td></td><td></td><td></td><td>σι</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>a</td><td></td><td></td><td></td><td>ω</td><td> 01</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Φ</td><td></td><td></td><td></td><td>03 rd</td><td>un LO σι</td><td> $</td><td></td><td></td><td> 03</td><td></td><td></td><td>A C3</td><td></td><td></td><td>A</td><td>a</td><td>rd</td><td></td><td></td><td rowspan="2">un</td><td></td><td></td><td></td><td></td><td>TT LO</td>

<td> 5?</td><td></td><td></td><td></td><td></td><td>OI</td><td></td><td></td><td></td><td></td><td></td><td></td><td>CQ</td><td>un</td><td>en</td><td>rd</td><td></td><td>fe</td><td></td><td></td><td rowspan="2">un</td><td></td><td></td><td rowspan="2">CQ 00</td><td></td>

<td>Φ</td><td>A</td><td>S</td><td></td><td>rd</td><td>P</td><td></td><td></td><td>fe</td><td></td><td>g</td><td>OI</td><td>a</td><td> §</td><td></td><td>rd</td><td>n</td><td></td><td></td><td rowspan="2">A cq £</td><td>te</td><td>te</td><td>e</td><td>s</td>

<td> $8</td><td> §</td><td>s</td><td>CQ</td><td> 8</td><td> §</td><td></td><td>b</td><td> §</td><td>y</td><td>s</td><td>i</td><td>fe CQ</td><td>e</td><td>á</td><td>δ</td><td>A CQ</td><td>g</td><td> |3</td><td>ω</td><td></td><td> 2</td><td> 0</td><td>feS</td><td>P 0</td>

<td>«i Ί</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>si</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Id Ap</td><td> 03</td><td>OI</td><td>OI</td><td> 03</td><td>OI</td><td> 03</td><td> 03</td><td> 03</td><td> 03</td><td> 03</td><td>OI</td><td>OI</td><td> 03</td><td> 03</td><td> 03</td><td>OI</td><td> 03</td><td> 03</td><td>OI</td><td>o»</td><td>OI</td><td> 03</td><td> 03</td><td> 03</td><td>OI</td>

<td> « &lt;</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>s</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>a 8 o «</td><td>w g</td><td>cq g</td><td></td><td>ω g</td><td>ω §</td><td>cq g</td><td>ω g</td><td>CQ</td><td>CQ g</td><td>CQ g</td><td>CQ g</td><td>CQ g</td><td>CQ g</td><td>CQ g</td><td>CQ g</td><td></td><td>CQ g</td><td>CQ §</td><td>CQ g</td><td></td><td>CQ g</td><td>CQ g</td><td> %</td><td>CQ g</td><td>CQ g</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>un</td><td>un</td><td>en</td><td>A</td><td>P</td><td>o</td><td> 3*</td><td>LO</td><td>LO</td><td>P</td><td>σι</td><td>P</td><td>o</td>

<td> *8</td><td></td><td></td><td>σι</td><td>o</td><td>o</td><td> 3¹</td><td>p</td><td> 03</td><td>LO</td><td>o</td><td>o</td><td>LO</td><td>P</td><td> 3»</td><td> 3»</td><td>O</td><td> 00</td><td>LO</td><td> 3*</td><td> 3*</td><td></td><td>A</td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>σι</td><td> 03</td><td>LO</td><td> 03</td><td>rd</td><td>A</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td> 03</td><td></td><td></td><td></td><td></td><td> 00</td><td>LO</td><td>LO</td><td>LO</td><td>LO</td><td>un</td><td> 3*</td><td>A</td><td>A</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>OI</td><td>O)</td><td>OI</td><td>OI</td><td> 03</td><td>OI</td><td>OI</td><td> 03</td><td>rd</td><td>rd</td><td> «—1</td><td>rd</td><td>rd</td><td>r3</td><td>rd</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>A</td><td>rd</td><td>A</td><td></td><td>A</td>

<td>Φ &lt;0 0 cu h a</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Q</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>en</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>co</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>«d</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>σι</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>a s</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>p 03</td><td></td><td></td><td></td><td></td><td></td><td>CP fe</td><td></td><td></td><td></td><td></td><td></td><td></td><td>un σ\</td><td></td><td></td>

<td> &amp;</td><td></td><td>f?</td><td>i—1</td><td></td><td></td><td></td><td>_n</td><td></td><td></td><td>O</td><td> 10</td><td></td><td></td><td>a</td><td></td><td>W 03</td><td></td><td>pj</td><td></td><td>un</td><td></td><td>pl</td><td> 3·</td><td></td><td>un</td>

<td>¡s</td><td>s</td><td>g</td><td>S</td><td>£j</td><td></td><td> 03</td><td>L«¡</td><td> ..</td><td> 3</td><td>rd</td><td> 5</td><td>fe</td><td></td><td>un</td><td></td><td>3* y</td><td>en C &gt;</td><td></td><td> 8</td><td>h</td><td>g</td><td rowspan="2">e</td><td>O</td><td>g</td><td>S</td>

<td> $8</td><td>w</td><td> 8</td><td>s</td><td>i</td><td> 3</td><td> §</td><td> §</td><td>i</td><td>e</td><td> §</td><td> 1</td><td>s</td><td> £</td><td>e</td><td>fes</td><td> 6</td><td> §</td><td></td><td>A H</td><td>y</td><td>fe</td><td> 3</td><td>ci</td><td></td>

<td>H 8</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>φ (0</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>•0 A</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>:dv PI</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>ir</td><td>un</td><td>in</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td><td>un</td>

ιη o

rH

126

<img file="MX366164B_D0028.tif" />

<td>Gen de siembra</td><td>i</td><td>_l</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>TPM2</td><td></td><td></td><td></td><td> !</td><td></td><td></td><td></td><td></td><td></td><td>TFM2</td><td></td><td></td><td></td><td></td>

<td>Peso de la sonda</td><td>tn tí* 00 es</td><td>tí* o fS 00 CS</td><td>rd O rd 00 rs</td><td>LD CS en r- rs</td><td>σ ω r» r· rs</td><td>00 m tí* CS</td><td>&lt;Λ Γ- L0 LD rs</td><td>0Ί O tí* LD CS</td><td>σ\ r- σ\ tn es</td><td>ro o LD tn CS</td><td>LO r- tn tí* rs</td><td>ro tn ro tí* rs</td><td>00 σι rs tí* rs</td><td>00 tn tí* ro rs</td><td>rd σι o ro CS</td><td>r- 00 O) rs rs</td><td>rt LD LD rd rs</td><td>σ\ LD tn rd rs</td><td>tí* LD rt rd CS</td><td>LD Γ- ΟΟ O CS</td><td>00 LD tí* O CS</td><td>00 σ\ LD σ rd</td><td>(O LO C* 00 rd</td><td>tí* 00 rs 00 rd</td><td>r- rd O 00 rd</td>

<td>1 Q 8</td><td>a 1</td><td>00 LO tí* σ\ es y</td><td>g</td><td></td><td>ft</td><td>00 g a</td><td>g</td><td> §</td><td>rd</td><td>i</td><td>ω g g</td><td>rd</td><td>r&gt; 1 En</td><td> !</td><td></td><td>σ</td><td>H</td><td> 1</td><td></td><td> §</td><td>en</td><td>gj</td><td>00 i eS</td><td>í</td><td></td>

<td>d SÍ</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>Gen de j siembra |</td><td>rd X 0 H</td><td>«—1 X a</td><td>tí a</td><td>tí O H</td><td>tí a</td><td>tí a</td><td>rd §</td><td>rd En a</td><td>rd En O K</td><td>rd En 0 H</td><td>rd §</td><td>£ a</td><td>rd &amp; H</td><td>g H</td><td>rd §</td><td>rd §</td><td>rd §</td><td>rd En O H</td><td>rd Efe 0 H</td><td>tí 0 H</td><td>rd En a</td><td>rd §</td><td></td><td></td><td>C^</td>

<td>Peso de la sonda</td><td>tí*</td><td>tí*</td><td>tí*</td><td>tí*</td><td>tí*</td><td>tí*</td><td>tí*</td><td>tí*</td><td>tí»</td><td>tí*</td><td>ro</td><td>ro</td><td>fO</td><td>ro</td><td>ro</td><td>rs</td><td>rs</td><td>CS</td><td>CS</td><td>CS</td><td>rs</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>1 Q 8 J</td><td> 00</td><td>Cj</td><td>o rd rs Md b rd u</td><td>u 3</td><td>rd</td><td>oo</td><td>a §</td><td>en</td><td>g</td><td>i</td><td>rd 1</td><td>m</td><td>ro ro Md 8 rt O</td><td> 1</td><td>« in tí x X</td><td> £0</td><td>i</td><td>Ch</td><td>en i</td><td>o Γ- Ud o 0</td><td>M</td><td>rd</td><td>i</td><td>H</td><td></td>

<td>sí</td><td>rs</td><td>rs</td><td>rs</td><td>CS</td><td>rs</td><td>CS</td><td>rs</td><td>rs</td><td>rs</td><td>rs</td><td>rs</td><td>rs</td><td>rs</td><td>rs</td><td>rs</td><td>rs</td><td>rs</td><td>rs</td><td>CS</td><td>CS</td><td>CS</td><td>CS</td><td>rd</td><td>rd</td><td>rd</td>

<td>Gen de siembra</td><td>en §</td><td>en §</td><td>en a</td><td>en a</td><td>S</td><td> 1</td><td>en a</td><td>en §</td><td>en o</td><td>en a</td><td>en S</td><td></td><td>en a</td><td>en a</td><td>en a</td><td>en §</td><td></td><td>en a</td><td>en §</td><td>en §</td><td>en a</td><td>en a</td><td>en a</td><td>en a</td><td> 1</td>

<td>Peso de la sonda</td><td>tn &lt;n tn o rd</td><td>00 rd rd O rd</td><td>rd r- LD 00</td><td>co &gt; tí* 00</td><td>O o o r-</td><td>00 tí* LD LD</td><td>co tí* σ&gt; tn</td><td>tn rd Γ- tn</td><td>&gt; in LD tn</td><td>rd rd LD tn</td><td>in m in rt</td><td>tn Φ t tí*</td><td>rd rd LD tí*</td><td>fft ro tí* tí*</td><td>rs σι ro tí*</td><td>ro tí* CS tí*</td><td>LO LD σ&gt; ro</td><td>rs &lt;n rt (O</td><td>LD ro CS ro</td><td>rt LD rd ro</td><td>CS tí* o ro</td><td>rd rd O ro</td><td>rd 00 CO es</td><td>rd rt CO CS</td><td>tí* rs r- rs</td>

<td>1 Q 8 $8</td><td>3 á</td><td>m N</td><td> 3</td><td> 9</td><td></td><td>s i</td><td></td><td></td><td>w</td><td> %</td><td> 1</td><td>es ^s</td><td>i</td><td>rs</td><td>f a a</td><td></td><td>g</td><td>gs</td><td>LD tí* 00 0&gt; rs rd O O H</td><td>ro</td><td>rd §</td><td>1 a</td><td>rd CS</td><td> 1</td><td> 1</td>

<td>Id del Apilado</td><td>tn</td><td>tn</td><td>tn</td><td>in</td><td>tn</td><td>m</td><td>tn</td><td>tn</td><td>tn</td><td>tn</td><td>tn</td><td>rt</td><td>rt</td><td>tn</td><td>tn</td><td>tn</td><td>rt</td><td>tn</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td>

ιη ιη γΗ o

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<td>Gen de siembra</td><td></td><td></td><td></td><td></td><td>_l</td><td></td><td></td><td></td><td></td><td></td><td></td><td>_l</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Peso de la sonda</td><td>m en Γ- Γ- Η</td><td>&lt;n ΙΛ co r- rd</td><td>co o fO 0* rd</td><td>&lt;n in co co rd</td><td>o t- in co rl</td><td>in 00 LO rd</td><td>co P co P H</td><td>co P in m rd</td><td>σ» Γ- P m rd</td><td>m P O m rd</td><td>00 00 &lt;n n rd</td><td>P m m OI rd</td><td>OI rd H OJ rd</td><td>OJ c— &lt;n rd rd</td><td>m m 00 rd rd</td><td>&lt;n P OJ rd rd</td><td>P c- σ\ o rd</td><td>co &lt;n t— o rd</td><td>Γ- ΟΟ co o rd</td><td>OI co en o rd</td><td>00 co o o H</td><td>m o en σι</td><td>OI H f- &lt;n</td><td>in H m en</td><td>O &lt;n 01 &lt;n</td>

<td>Gen Co- expresado</td><td>en</td><td>H</td><td>H</td><td></td><td></td><td>H υ</td><td>s g</td><td>i</td><td></td><td>03 ω H</td><td>r^</td><td>1 ω</td><td></td><td></td><td>i</td><td>i</td><td></td><td> 1</td><td> §</td><td>&lt;n r- OJ rd O o rd 8 n 3 co</td><td></td><td>_s</td><td></td><td></td><td></td>

<td>Id del Apilado</td><td>rd</td><td>rl</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>rd</td><td>H</td><td>H</td><td>H</td>

<td>Gen de sienbra</td><td></td><td></td><td></td><td></td><td></td><td> 0;</td><td></td><td>g H</td><td></td><td></td><td>0 H</td><td></td><td></td><td>r^</td><td></td><td>H</td><td></td><td></td><td>H</td><td></td><td></td><td>H</td><td></td><td>g H</td><td></td>

<td>Peso de la sonda</td><td>rd CO CO</td><td>OI m co</td><td>σ P co</td><td>t- 01 co</td><td>P 01 CO</td><td>rd rd CO</td><td>OI O co</td><td>O P in</td><td>r- OJ in</td><td>01 σ&gt; P</td><td>rd σ P</td><td>rd CO P</td><td>P m P</td><td>m OJ P</td><td>P CO m</td><td>rd m m</td><td>01 OJ H</td><td>03 OI m</td><td>Γ- Η m</td><td>Γ- Η m</td><td>P H n</td><td>H O H</td><td>00 00 OI</td><td>Γ- ΟΟ 01</td><td>OJ CO OJ</td>

<td>1 a 5 6 $3</td><td>Λ</td><td> 1</td><td></td><td>g</td><td> !</td><td> 0^</td><td>m §</td><td>g</td><td>J</td><td>rd</td><td>ω B</td><td>H</td><td>s Vi</td><td>rd</td><td>00 1 S</td><td>i</td><td>_l</td><td>_l</td><td>co e a</td><td>H</td><td>H</td><td>H</td><td>_l</td><td>í</td><td></td>

<td>Η 3 g 2 se</td><td>OI</td><td>OI</td><td> 01</td><td>OJ</td><td>OJ</td><td>OJ</td><td>OI</td><td>OI</td><td>OI</td><td>n</td><td>OI</td><td>OI</td><td> 01</td><td>OI</td><td>OI</td><td>OI</td><td>OJ</td><td> 01</td><td> 03</td><td>OI</td><td>OI</td><td>OI</td><td> 01</td><td> 03</td><td>OJ</td>

<td>Gen de siembra</td><td>w b</td><td></td><td>w §</td><td>W §</td><td></td><td>ω B</td><td>W B</td><td>W B</td><td> §</td><td>w B</td><td>ω B</td><td>w B</td><td>ω B</td><td></td><td>w B</td><td>w B</td><td></td><td>g</td><td>a B</td><td></td><td></td><td></td><td>ω B</td><td>w B</td><td></td>

<td>Peso de la sonda</td><td>P o r— n</td><td>P o P OI</td><td>P Γ- m OI</td><td>Γ9 in OI OI</td><td>co 00 O OI</td><td>co P O OI</td><td>co en &lt;n rd</td><td>rd en co rd</td><td>o n co rd</td><td>o en co rd</td><td>t- &lt;n Γ- rd</td><td>co co r- rd</td><td>OI 00 co rd</td><td>co &lt;n w rd</td><td>&lt;n Γ- ιη rd</td><td>rd rd ID rd</td><td>ro in P rd</td><td>rd co rd</td><td>in Γ- Ol rd</td><td>in H OI H</td><td>o en o H</td><td>co Γ- ΟΟ</td><td>r- co 00</td><td>H P 00</td><td>00 OI oo</td>

<td>i tí 3 $3</td><td></td><td>g</td><td>P o &lt;n &lt;*&gt; co</td><td> 1</td><td>&lt;n y</td><td> §</td><td></td><td>P OI g o</td><td>CO 1</td><td>1 e2</td><td>rd i</td><td> »</td><td>M</td><td>en 3</td><td> 1</td><td>H</td><td>O</td><td>s</td><td>s w</td><td> §</td><td></td><td></td><td>o</td><td>CO co H Md 8 CO U</td><td>o</td>

<td>si se</td><td>in</td><td>in</td><td>in</td><td>Ul</td><td>LO</td><td>LD</td><td>in</td><td>m</td><td>in</td><td>m</td><td>m</td><td>m</td><td>m</td><td>in</td><td>m</td><td>in</td><td>in</td><td>in</td><td>in</td><td>in</td><td>in</td><td>in</td><td>in</td><td>en</td><td>in</td>

LD in

H

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<td>Gen de siembra</td><td>g</td><td>C}</td><td>g</td><td>CJ g Et</td><td>g</td><td>g</td><td>i</td><td>g</td><td>g</td><td>g</td><td></td><td>g</td><td>g</td><td>g</td><td>g</td><td> 0</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td>

<td>Peso de la sonda</td><td>0 m 03 CO</td><td>03 rd 03 09</td><td>0 03 &gt; CO</td><td>Tí 0 p* co</td><td> 0 03 0 0</td><td> 0 0 0</td><td>0 rd M* 0</td><td>p· CJ</td><td>0 í 0 0</td><td>0 CJ 0</td><td>0 TÍ CJ 0</td><td>0 rd P· 0</td><td>«· Tí 0 0</td><td>0 P- *· 0</td><td>r*&gt; CJ 03 »í</td><td>C1 CJ 03 Tí</td><td>o 0 0 Tí</td><td>m 0 p· -i</td><td>O «í 0 «í</td><td>03 03 «· Tí</td><td>0 en rd Tí</td><td>0 rd 0 en</td><td>o 03 Tí en</td><td>0 en Tí en</td><td>rd Tí rd m</td>

<td>Gen Co- expresado</td><td>i</td><td> !</td><td>0 «í CJ 0</td><td>τρ 0 0 0 Tí 0</td><td></td><td> 0 %</td><td>Si É</td><td> §</td><td>H</td><td></td><td>a H</td><td></td><td>í? CU w CJ</td><td>0 N %</td><td> 1</td><td></td><td>i</td><td>g 1</td><td></td><td></td><td> 1</td><td>δ</td><td>i</td><td> 1</td><td>w</td>

<td>Sil sí</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>® Ό J O Qt</td><td></td><td></td><td></td><td>H</td><td></td><td>H</td><td>g H</td><td>H</td><td>H</td><td>H</td><td>H</td><td></td><td></td><td>P^</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>H</td><td>g H</td><td>C H</td><td></td>

<td>&lt;tf -· 8^1 Φ Φ 0 CU Ό TO</td><td>Tí 0 CJ</td><td>0 0 CJ</td><td>0 0 Cl</td><td>0 0 CJ</td><td>rd n CJ</td><td>CJ CJ CJ</td><td>O CJ CJ</td><td>0 O CJ</td><td>Tí O CJ</td><td>&gt; 0 rd</td><td>0 0 rd</td><td>0 0 rd</td><td>Tí 0 rd</td><td>Tí P· rd</td><td>CJ rd</td><td>P' 0 rd</td><td>0 0 rd</td><td>CJ Tí rd</td><td>0 en rd</td><td>CJ en rd</td><td>0 CJ rd</td><td>CJ rd rd</td><td>O rd rd</td><td>03 O rd</td><td>rd O rd</td>

<td>Gen Co-expresado</td><td>rd</td><td></td><td>I</td><td>i</td><td> 0</td><td></td><td>rd H W</td><td>Tí CJ 0</td><td></td><td></td><td>_l</td><td>CJ i</td><td> §</td><td>P· 8 b</td><td></td><td> 0</td><td>i</td><td> §</td><td></td><td> !</td><td></td><td> !</td><td>9 i</td><td>0 0 Tí 03 CJ</td><td></td>

<td>d 3 2</td><td>CJ</td><td>OI</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td><td>CJ</td>

<td>Gen de siembra</td><td>ω §</td><td>W a</td><td>ω a</td><td>W a</td><td> %</td><td>w a</td><td>ω a</td><td>w a</td><td>w a</td><td>ω a</td><td></td><td>w a</td><td>ω §</td><td>co a</td><td>w ω B</td><td></td><td>M a</td><td>co a</td><td>10 a</td><td>w §</td><td>W a</td><td>w a</td><td>CQ a</td><td>w</td><td></td>

<td>Peso de la sonda</td><td>0 CJ CO</td><td>CJ o 0</td><td>rd CJ c-</td><td>o &gt; 0</td><td> 0 0 0</td><td>CO 0 0</td><td>r- 0 0</td><td>03 σ\ Tí</td><td>0 p* Tí</td><td>p- rd TÍ</td><td>0 O -í</td><td>03 0 m</td><td>0 0 m</td><td>Tí 0 m</td><td>o 0 en</td><td>en en en</td><td>o CJ en</td><td>CJ o en</td><td>Tí 03 CJ</td><td>0 0 CJ</td><td>03 «í CJ</td><td>03 en CJ</td><td>0 0 CJ</td><td>CJ 0 CJ</td><td>rd CJ CJ</td>

<td>1 (0 QJ J $8</td><td> 0</td><td></td><td>3 rd y w</td><td>H</td><td> 1</td><td> !</td><td></td><td> 3</td><td>H</td><td> 3 §</td><td>m 0 u-i 8 rd 0</td><td>í</td><td>g</td><td></td><td>en</td><td></td><td>b a</td><td> § §</td><td>en s S</td><td></td><td> !</td><td>rd</td><td>O</td><td>i</td><td>S</td>

<td>-g § Ό rd 3 2</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td>

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<td>3 J u u</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>JN</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>O¡</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td>

<td>3 ° § 3 m o 0. r-l »</td><td>O ftí tn es</td><td>10 o tí· CS</td><td>10 P- m es</td><td>H ftí es es</td><td>σι es o es</td><td>en es o es</td><td>r- o o es</td><td>m 10 en i-1</td><td>tn co Γ- Η</td><td>O CS Γ- Η</td><td>o o Γ- Η</td><td>en un tí* H</td><td>10 &lt;n es H</td><td>Γ- ΟΟ rs H</td><td>10 tn es H</td><td>10 es es r-1</td><td>o Γ- Η H</td><td>en 10 o H</td><td>tn 10 o H</td><td>o 10 o H</td><td>Γ- Η en</td><td>00 00 e»</td><td>H Γ— CO</td><td>en 10 00</td><td>o tn co</td>

<td>Gen Co- expresado</td><td>in 1</td><td> 9</td><td>es A g</td><td>co σι es t-l O O (-1 Q 10 3 tí*</td><td> §</td><td>LA</td><td>tí· o en ftí ω</td><td>es i</td><td>H es £</td><td></td><td>es a 8</td><td>H</td><td>a en</td><td>en id</td><td>H I</td><td>A g</td><td>_§</td><td></td><td>8 tí</td><td>en 8</td><td>tí· CS i</td><td></td><td>g</td><td>U</td><td>o</td>

<td>d 52</td><td>H</td><td>r-l</td><td>H</td><td>i—1</td><td>H</td><td>i-l</td><td>H</td><td>i—1</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>5 tí</td><td>P^ H</td><td>H</td><td>r^ H</td><td>P^ H</td><td>P^ H</td><td></td><td></td><td>H</td><td>r^</td><td>0 H</td><td>P^ H</td><td>i</td><td>r^</td><td></td><td>g H</td><td></td><td>P^ H</td><td>g H</td><td></td><td>P^</td><td>H</td><td></td><td>H</td><td>P^ H</td><td>H</td>

<td>Peso de la sonda</td><td> 10 10</td><td>rs 10</td><td>m un</td><td>LO tí·</td><td>tí· tí·</td><td>ftí tí*</td><td>i-l tí*</td><td>00 en</td><td>tí· ftí</td><td>ftí ftí</td><td>O ftí</td><td>oo ÍS</td><td>P- cs</td><td>es CS</td><td>es es</td><td>en H</td><td>en H</td><td>m H</td><td>t- H</td><td>Γ- Η</td><td>H H</td><td>&lt;n</td><td>en</td><td>en</td><td>CO</td>

<td>1 Q § Is</td><td>i</td><td>es 1</td><td></td><td> 0</td><td></td><td>ftí A</td><td></td><td></td><td>m N §</td><td>s</td><td>10 00 H 4-1 8 10 u</td><td> -_t</td><td>H Ω B</td><td>un tí· 4-1 8 10 H U</td><td></td><td>tn</td><td>(tí A 3</td><td>es</td><td>H</td><td>CS 8</td><td>H</td><td>ftí §</td><td></td><td>H g</td><td>H</td>

<td>31 •0 H 5 2</td><td>CS</td><td>CS</td><td>es</td><td>es</td><td>es</td><td>es</td><td>CS</td><td>&lt;s</td><td>es</td><td>rs</td><td>es</td><td>es</td><td>CS</td><td>CS</td><td>es</td><td>es</td><td>es</td><td>es</td><td>es</td><td>es</td><td>es</td><td>es</td><td>CS</td><td>CS</td><td>es</td>

<td>Gen de | siembra |</td><td>tn g</td><td>en §</td><td>en g</td><td>tn 8</td><td>en 8</td><td>en g</td><td>en 8</td><td>en 8</td><td>en 8</td><td>en g</td><td>en 8</td><td>en 8</td><td>en 8</td><td>en 8</td><td>en g</td><td>tn g</td><td>en g</td><td>en g</td><td></td><td>en g</td><td>en g</td><td></td><td>en g</td><td>en g</td><td> 1</td>

<td>Peso de la sonda</td><td>m t-l es</td><td>ÍS co t—1</td><td>i—1 00 H</td><td>ID Γ- i—l</td><td>m Γ- Η</td><td>10 10 r-l</td><td>tí· 10 r-1</td><td>10 in H</td><td>m en H</td><td>ÍS ftí H</td><td>10 CS H</td><td>tn σι</td><td>tí· en</td><td>H en</td><td>Γ- ΟΟ</td><td>en tí·</td><td>co tí·</td><td>m tí*</td><td>o tí»</td><td>Γ- ΓΟ</td><td>o ftí</td><td>σι es</td><td>H CS</td><td>10 H</td><td>es H</td>

<td>Gen Co-expresado</td><td>es t—l i</td><td> 5</td><td>E 8</td><td>H en</td><td></td><td>1 g</td><td></td><td>H</td><td> 1</td><td>O tí· U-l b es u</td><td>H H H g 8</td><td>tí· £tí</td><td>g</td><td>H A</td><td>i</td><td>i</td><td>H A</td><td>o H A</td><td>CS ω</td><td>CS 1</td><td>u</td><td>CS n 8</td><td>O l</td><td>H</td><td>i</td>

<td>Id del Apilado</td><td>m</td><td>tn</td><td>un</td><td>un</td><td>tn</td><td>in</td><td>tn</td><td>tn</td><td>tn</td><td>tn</td><td>tn</td><td>tn</td><td>tn</td><td>un</td><td>tn</td><td>tn</td><td>tn</td><td>un</td><td>un</td><td>un</td><td>in</td><td>un</td><td>un</td><td>un</td><td>tn</td>

ιη tn

Η

130

<td>Gen de siembra</td><td></td><td></td><td>_l</td><td>_l</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>g</td><td></td><td></td><td></td>

<td>Peso de la sonda</td><td>Φ σι 0-</td><td>Oí to r-</td><td>m σι to</td><td>o Φ to</td><td>ΡΊ 1*) to</td><td>o o to</td><td>co co Φ</td><td>&lt;n OI Φ</td><td>to OI Φ</td><td>OI o Φ</td><td>o to en</td><td>•Φ to &lt;n</td><td>σι &lt;n en</td><td>P- OI en</td><td>to OI «n</td><td>i—1 O en</td><td>o o en</td><td>co en 04</td><td>Φ to OI</td><td>CO Φ OI</td><td>P- OI OI</td><td>r-l «—4 OI</td><td>O· o OI</td><td>Φ σι r-l</td><td>en co r-4</td>

<td>1 Q 8 1 8 1</td><td>to</td><td> §</td><td> 1</td><td>i</td><td>to</td><td>i en</td><td></td><td></td><td></td><td>i</td><td></td><td>a 1</td><td> £</td><td>OI r4 %</td><td>i</td><td> !</td><td>H</td><td></td><td> !</td><td>§ á</td><td>o H</td><td> 1</td><td></td><td>fe 8</td><td></td>

<td>Id del Apilado</td><td>«—i</td><td>r4</td><td>t-4</td><td>t-l</td><td>r4</td><td>i—t</td><td>c4</td><td>i—1</td><td>r4</td><td>τ—1</td><td>r4</td><td>c4</td><td rowspan="2">t-4</td><td rowspan="2">r4 a to</td><td rowspan="2">r4 §</td><td rowspan="2">«—4 a to</td><td>i—4</td><td>H</td><td>r-4</td><td>i—1</td><td>H</td><td>r-l</td><td>r4</td><td>H</td><td>r-l</td>

<td>Gen de 1 siembra |</td><td></td><td></td><td>P^</td><td></td><td>P^ H</td><td></td><td>P^</td><td>P^</td><td>P^</td><td>P^</td><td>a to</td><td>a to</td><td>a to</td><td>a to</td><td>a É</td><td>a to</td><td>i</td><td>a to</td><td>l</td><td>a</td><td>a to</td>

<td>Peso de la sonda</td><td>P-</td><td>to</td><td>to</td><td>to</td><td>n</td><td> (*)</td><td> 04</td><td>OI</td><td>H</td><td>r4</td><td>σι en &lt;—4 P- Φ</td><td>to to o Γ- Φ</td><td>OI o o P- Φ</td><td>Γ* to en to Φ</td><td>Φ Γ- ΟΟ to Φ</td><td>H Γ- ΟΟ to Φ</td><td>&lt;n o P- to Φ</td><td>σι σι to to. Φ</td><td>co OI Φ to Φ</td><td>Φ O Φ to Φ</td><td>to to en to Φ</td><td>co r- OI to Φ</td><td>OI σι 00 to Φ</td><td>σ Γ- ΟΟ to Φ</td><td>Φ p- Γ* to Φ</td>

<td>Gen Co-expresado</td><td></td><td> !</td><td> 1</td><td>to r4 to</td><td>i</td><td></td><td></td><td>en fe</td><td>_i</td><td>r4 s a</td><td> § £</td><td>co to Φ en P4 p- 3</td><td> 3 1</td><td>i</td><td>i</td><td>i—1 en H a</td><td>OI i</td><td>a to</td><td>&lt;n a en 2</td><td> ?</td><td> |</td><td>g</td><td></td><td></td><td>r4</td>

<td>K 8</td><td>OI</td><td>OI</td><td>OI</td><td>OI</td><td>OI</td><td>OI</td><td>OI</td><td>OI</td><td>OI</td><td>OI</td><td>i-4</td><td>r4</td><td>r-l</td><td>i—4</td><td>«—I</td><td>r4</td><td>r-l</td><td>H</td><td>r4</td><td>r-l</td><td>i—1</td><td>r4</td><td> «—1</td><td>«H</td><td>t-4</td>

<td>Gen de siembra</td><td>en 8</td><td>en a</td><td>en a</td><td>en §</td><td>to §</td><td>en §</td><td>en §</td><td></td><td>w §</td><td>en S</td><td>m a</td><td>en Ω</td><td>en a</td><td>t—4 8</td><td>t—4 8</td><td> 1</td><td></td><td>r-l 8</td><td>H</td><td>r-l 8</td><td>t—1 i</td><td>H 8</td><td></td><td>i—4 0</td><td>H</td>

<td>Peso de la sonda</td><td>Oí r-1</td><td>r-4 c-I</td><td>r-4 r-t</td><td>o rH</td><td>σι</td><td>to</td><td>to</td><td>en</td><td>en</td><td>&lt;*l</td><td>OI</td><td>C4</td><td>r-4</td><td>φ</td><td>φ</td><td>Φ</td><td>Φ</td><td>m</td><td>ΡΊ</td><td>en</td><td>OI</td><td>oí</td><td>OI</td><td> 04</td><td>OI</td>

<td>8 í 88</td><td></td><td>Φ</td><td>g</td><td>to Φ U-l 8 to r4 U</td><td></td><td>i-4 1</td><td>i</td><td></td><td>3 8 fe</td><td>s fe</td><td>_s</td><td>5¡ i</td><td>to a a</td><td> 1</td><td>i</td><td> 8</td><td>í</td><td>ω</td><td></td><td>co 8 a</td><td>i</td><td></td><td></td><td>en a</td><td> 2 8</td>

<td>Id del Apilado</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>i~4</td><td>i—f</td><td>H</td><td>r4</td><td>r-4</td><td>t-l</td><td></td><td>t—1</td><td>r-1</td><td> &lt;-4</td><td>c-4</td><td>H</td>

ιη o

Γ1

LD

131 ^; '55

<td>Gen de siembra</td><td>_l</td><td></td><td>p</td><td></td><td></td><td></td><td>_l</td><td></td><td></td><td></td><td>p</td><td></td><td></td><td></td><td>d</td><td></td><td>d</td><td></td><td></td><td></td><td></td><td>g</td><td></td><td></td><td></td>

<td>Peso de la sonda</td><td>H 00 rd</td><td>Γ- Γ- Η</td><td>in Γ- Η</td><td>d Γ- Η</td><td>d kO H</td><td>kD H</td><td>H in H</td><td>O d H</td><td>CO d H</td><td>kD d H</td><td>kD d H</td><td>d d rd</td><td>d d H</td><td>Γ- Ο H</td><td>sf OI</td><td>H oí</td><td>O 01</td><td>01 d</td><td>H d</td><td>co sf</td><td>d sf</td><td>kD d</td><td>^· d</td><td>*· d</td><td>d d</td>

<td>3 &lt;0 c m</td><td>1 ω</td><td>d Ü5 §</td><td></td><td>d 63</td><td></td><td> !</td><td>d kD H H 0</td><td>w</td><td>i</td><td>H</td><td>H H H e b</td><td>d H</td><td> 1</td><td>H</td><td> !</td><td>gl a</td><td>o sf kt-l 8 d o</td><td> !</td><td></td><td>O B</td><td>i</td><td>d w</td><td>d §</td><td>a d</td><td>d !</td>

<td>si s#</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td rowspan="2">H a d</td><td rowspan="2">H a d</td><td rowspan="2">H a d</td><td>H</td><td>H</td><td>H</td>

<td> •8</td><td>a É</td><td></td><td>a LC</td><td>a d</td><td>a d</td><td>a d</td><td>a d</td><td> 2*</td><td></td><td></td><td>a d</td><td>a d</td><td>l</td><td>a d</td><td>a d</td><td> §</td><td>a d</td><td>a É</td><td>a É</td><td>a d</td><td>a É</td><td>a Uj</td>

<td>Peso de la sonda</td><td>σι rd d d sf</td><td>σι σι Cl -3· sí&lt;</td><td>kD Cl H sf sf</td><td>σι d co d sf</td><td>H O d s3*</td><td>σι 09 d d sf</td><td>c- sf 01 d sf</td><td>d 00 a</td><td>sí· O a</td><td>Sf 09 CO O sf</td><td>00 H H O sf</td><td>kD d co 01 d</td><td>01 d d Ok d</td><td>sí· H sí· oo d</td><td>kD Sí» d sr d</td><td>00 kD OI d d</td><td>d kD 01 d d</td><td>d d kD d d</td><td>co d H d d</td><td>d C-» o d d</td><td>d 01 d d d</td><td>d H Γ- Η d</td><td>01 o d OI d</td><td>co kD H σ» d</td><td>Γ- ΙΟ sf 00 d</td>

<td>1 a 8 $</td><td>s Cl §</td><td>^d</td><td>g</td><td>H !</td><td>d</td><td> 1</td><td></td><td>H</td><td>H</td><td></td><td></td><td> §</td><td>H 1 w</td><td> 1</td><td>r- a Pm</td><td>a d</td><td>i</td><td>H</td><td>_i</td><td>d</td><td> 1</td><td></td><td></td><td>d</td><td>r-i 1</td>

<td>Id del Apilado</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td rowspan="2">H</td><td rowspan="2">H</td><td rowspan="2">H</td><td rowspan="2">H d 8</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>Ί §1 3 n</td><td>rd 8</td><td>H</td><td>H 8</td><td>H i</td><td>H 8</td><td>H 8</td><td>H 8</td><td> 1</td><td> 1</td><td>i</td><td>O</td><td> 1</td><td>i</td><td>i</td><td>i</td><td></td><td>i</td><td> 1</td><td>i</td><td>I</td><td></td>

<td>Peso de la sonda</td><td>&lt;s</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>-3· kD d</td><td>co d d</td><td>co d d</td><td>kD d d</td><td>d d d</td><td>o d d</td><td>O d d</td><td>O d d</td><td>CO sf d</td><td>C* &lt;3· d</td><td>d sf d</td><td>d d d</td><td>H d d</td><td>Γ- Η d</td><td>d H d</td><td>O rd d</td><td>OI o d</td><td>H o d</td>

<td>1 &lt;0 Φ Ϊ $5</td><td>rd 8</td><td></td><td>a É</td><td> !</td><td>CO kO sf 01 Cl Γ*</td><td> 1</td><td>d Λ d</td><td>H</td><td></td><td>H l</td><td>s d g</td><td>d W H g</td><td>_l</td><td>l!</td><td>_l</td><td>l</td><td>H 05 H</td><td>gj</td><td></td><td>H</td><td>i</td><td>i</td><td> 1</td><td>w</td><td>d</td>

<td>si sa·</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td>

ιη ο

γ4 ιη

Η

132

<img file="MX366164B_D0030.tif" />

<td> 8</td><td>OI i</td><td></td><td></td><td></td><td></td><td>_l</td><td></td><td></td><td>_l</td><td></td><td></td><td></td><td>_l</td><td>_l</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>•8 8 I 0 &lt;β 0 &amp; η η</td><td>i—1 0</td><td>σι rd</td><td>0 rd</td><td>rd rd</td><td>o rd</td><td>oo</td><td> 0</td><td>tí·</td><td>tí*</td><td> 0</td><td> 0</td><td> 0</td><td>rd</td><td>rd</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>$ ίδΙ</td><td>fd 8</td><td>H</td><td>H</td><td>s? 8</td><td>0 tí· Md £ 0 rd U</td><td>rd 0</td><td></td><td>tí* 0</td><td>rd 04 0 0</td><td></td><td> 5 % 04 04</td><td> 2 04</td><td>rd 0 Md 0 rd 0</td><td>rd 04 i</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>d S3</td><td>i—1</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Gen de siembra</td><td>a 0</td><td>a 0</td><td>a 0</td><td>a</td><td>a</td><td>a 0</td><td> § 0</td><td>a 0</td><td>a É</td><td>a 0</td><td>a 0</td><td>a 0</td><td>a 0</td><td>a 0</td><td>a 0</td><td>a 0</td><td>a 0</td><td>a 0</td><td>a</td><td>l</td><td></td><td>a 0</td><td>a 0</td><td>a</td><td>a</td>

<td>Peso de la sonda</td><td>0 rd 0 CO OI</td><td>co o rd 00 Oí</td><td>0 O rd 00 Oí</td><td>0 0 P- 0 Oí</td><td>rd Γ- 0 0 Oí</td><td>00 3 0 OI</td><td>σι OI rd 0 OJ</td><td>0 rd 0 0 OJ</td><td>r- Γ- tí· 0 OI</td><td>00 0 o 0 OJ</td><td>0 tí· o 0 O)</td><td>OO O Oí tí· 01</td><td>0 0 0 0 OI</td><td>0 tí· σι Oí Oí</td><td>0 0 Γ- OJ OI</td><td>0 00 rd OI 01</td><td>CO OI Γ- Η Oí</td><td>o σι 0 H 01</td><td>OJ o tí- H OJ</td><td>OI 0 σ» o Oí</td><td>o t- σι σι Η</td><td>00 00 0 σι H</td><td>σι σι o 0 H</td><td>0 H 00 CO H</td><td>0 Oí tí· 00 H</td>

<td> | $8</td><td> 0</td><td> 0</td><td> !</td><td>00 s w te</td><td> 1</td><td>_t</td><td> 1</td><td>Oí ω H</td><td></td><td>_l</td><td>H</td><td> ¡</td><td>0 00 σι r- Ol rd O O H</td><td>H</td><td>H</td><td>H</td><td>H u</td><td>i</td><td> 1</td><td>Ü3 8</td><td>m</td><td>£ a</td><td>00 H S</td><td>i</td><td>l</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>Η</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>Gen de siembra</td><td></td><td>i</td><td>i</td><td></td><td></td><td>i</td><td>i</td><td> 0</td><td> 0</td><td>Oí 0</td><td>OI 0</td><td>cS</td><td>OJ 0</td><td>i</td><td> 1</td><td>i</td><td>i</td><td></td><td>i</td><td> 1</td><td> !</td><td> 1</td><td>i</td><td></td><td>i</td>

<td>Peso de la sonda</td><td>cC &lt;n OI</td><td>Γ- ΟΟ Oí</td><td>0 00 OJ</td><td>0 00 OJ</td><td>Oí 00 Oí</td><td>0 c- OJ</td><td>0 Γ- OJ</td><td>0 Γ- Oí</td><td>0 Γ- Ol</td><td>o £- OJ</td><td>O Γ* 01</td><td>Oí 0 01</td><td>0 0 Oí</td><td>O 0 OI</td><td>r- 01 01</td><td>0 rd OJ</td><td>0 H Oí</td><td>σι o 01</td><td>P- o 01</td><td>tí· o Oí</td><td>OJ o OJ</td><td>OI o Oí</td><td>0 CO H</td><td>O 00 H</td><td>OJ Γ- Η</td>

<td>Gen Oo - expresado</td><td>00 e a</td><td> 0</td><td>_i</td><td>oí 04 0</td><td>a 0 a CQ</td><td>00 0 tí· σι OJ Γ- §</td><td>M</td><td>a 0</td><td>i</td><td> (</td><td> 1</td><td> 1</td><td>H</td><td>H</td><td>J</td><td>Γ- 8 04</td><td>0 oo σι 0- O) H O O H</td><td>i</td><td>0 i</td><td>H É</td><td>H 1</td><td> 0</td><td>H</td><td>H 1</td><td>ω £</td>

<td> $ 1 83</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>Η</td>

ιη ιη

Η

133

<td>3 J So</td><td></td><td></td><td></td>

<td>Peso de la sonda</td><td></td><td></td><td></td>

<td> 1 ¿4</td><td></td><td></td><td></td>

<td>Id del Apilado</td><td></td><td></td><td></td>

<td>Gen de sieicbra</td><td>a u&gt;</td><td>a</td><td> §</td>

<td>Peso de la sonda</td><td> 18066</td><td> 17638</td><td>co &gt; rd CO rd</td>

<td>s</td><td>MYH11</td><td>i</td><td>CDC42EP3</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td>

<td>•8 o 4 O a</td><td></td><td></td><td></td>

<td>Peso de la sonda</td><td></td><td></td><td></td>

<td>1 Q 8 . i</td><td></td><td></td><td></td>

<td>Id del Apilado</td><td></td><td></td><td></td>

ιη o

rd

LA rd

134

<img file="MX366164B_D0031.tif" />

Tabla 10

<td>Gen de siembra</td><td>MYBL2</td><td> 1</td><td> 1</td><td> 1</td><td>MYBL2</td><td>MYBL2</td><td>MYBL2</td><td> 1</td><td>i</td><td></td><td>MYBL2</td><td>MYBL2</td><td>MYBL2</td><td>MYBL2</td><td>i</td><td>MYBL2</td><td>i</td><td>MYBL2</td><td>MYBL2</td><td> 1</td><td>i</td><td>i</td><td></td><td></td>

<td>Peso de la sonda</td><td> 3824</td><td> 3767</td><td> 3765</td><td> 3706</td><td> 3650</td><td> 3636</td><td> 3589</td><td> 3582</td><td>σι 10 in ro</td><td> 3556</td><td> 3427</td><td> 3264</td><td> 3232</td><td> 3221</td><td> 3196</td><td> 3196</td><td> 3185 ¡</td><td> 3136</td><td> 3136</td><td> 3094</td><td> 3034</td><td>K0 ro Cl CJ</td><td> 2936</td><td>LO rd σι Cí</td>

<td>s 3 $ s</td><td></td><td></td><td>CDCA3</td><td>rd in rd 4-1 8 O CJ U</td><td>Cllorf41</td><td>CO σι 4d 8 σι O</td><td>KRT24</td><td>ABCC12</td><td>B3GNT4</td><td>rd H 3</td><td>RLTPR</td><td>KIF24</td><td>i</td><td>S H ►4</td><td></td><td>SECl</td><td>ω</td><td>SLC25A19</td><td>PRSS27</td><td>ODF3L2</td><td>0DZ4</td><td>RAD54L</td><td>KCNE1L</td><td>SBF1P1</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>Gen de siembra</td><td>O</td><td>O</td><td>O §</td><td>CDC20</td><td>O</td><td>O Cj</td><td>O CI</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O Cí</td><td>O</td><td>CDC20</td><td>O</td><td>O</td><td>O</td><td>O</td><td>CDC20</td>

<td>Peso de la sonda</td><td> 1997</td><td> 1991</td><td>o σι σι rd</td><td> 1983</td><td> 1965</td><td> 1965</td><td>ΙΛ 10 σι rd</td><td> 1965</td><td> 1955</td><td> 1910</td><td> 1862</td><td> 1821</td><td> 1765</td><td> 1681</td><td> 1529</td><td> 1507</td><td> 1507</td><td> 1374</td><td> 1220</td><td> 1063</td><td> 1052</td><td> 990</td><td>CJ ro σι</td><td> 757</td>

<td>£ a 8 $s 1</td><td>GPAT2</td><td>AVPR1B</td><td>MGC50722</td><td>tí CJ 0¡ 2</td><td>Cí Cí CJ 4-1 10 U</td><td>σι H</td><td>PRAMEF18</td><td>SLC5A9</td><td></td><td></td><td>i</td><td>PIA2G2F</td><td>C6orf25</td><td>CDC45</td><td></td><td>in CJ 04 H</td><td>ZDHHC19</td><td> 1</td><td>TACC3</td><td>TK1</td><td>el Md 8 w rd u</td><td></td><td>1 o</td><td>MCM10</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>Gen de 1 siembra |</td><td>O</td><td>O Cd</td><td>O 0</td><td>O</td><td>O</td><td> 0</td><td>O 0</td><td>O</td><td>O 0</td><td>O</td><td>CDC20</td><td>CDC20</td><td>CDC20</td><td>O</td><td>O</td><td>O</td><td>CDC20</td><td>O</td><td>CDC20</td><td>CDC20</td><td>O</td><td>O</td><td>O</td><td>CDC20</td>

<td>Peso de la sonda</td><td> 9758</td><td> 9758</td><td> 9758</td><td> 9674</td><td> 9671</td><td> 9671</td><td> 9328</td><td> 9316</td><td> 9178</td><td> 8987</td><td>U1 e* 00 00</td><td> 8875</td><td> 8554</td><td>10 ro 00</td><td> 8322</td><td> 8135</td><td> 7598</td><td>r· in r-</td><td> 7527</td><td> 7521</td><td> 7224</td><td> 7150</td><td> 6853</td><td> 10 00 &lt;0</td>

<td>Gen Co- expresado</td><td>NCAPH</td><td>O</td><td>£0 H</td><td>ESPL1</td><td></td><td>POC1A</td><td>1 KIF18B I_______</td><td>WDR62</td><td>i</td><td></td><td>rd S</td><td>SLC2A6</td><td>r^</td><td>FAM64A</td><td>9 ro rd i</td><td>H</td><td>KIFC1</td><td>| C9orfl00 i</td><td>KPS6KL1</td><td>i</td><td></td><td>LO Md 8 CJ u</td><td>«o</td><td>KRBA1</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

ιη ιη

135

<td>«, Μ si ¿5 η</td><td> 1</td><td> 1</td><td> 1</td><td>OI i</td><td></td><td>i</td><td> 1</td><td>i</td><td>i</td><td>i</td><td>rt i</td><td></td><td></td><td>i</td><td> 1</td><td> 1</td><td>i</td><td> 1</td><td> §</td><td>i</td><td> 1</td><td>oí i</td><td> 1</td><td>i</td><td></td>

<td>Peso de la sonda</td><td>co kP co OJ</td><td>OJ kO co OI</td><td>rt ct co OI</td><td>00 o co OI</td><td>ot ot Γ- ΟΙ</td><td>&gt; kp Γ- OJ</td><td>0J ko r- OJ</td><td>rt Oí 0- OI</td><td>O rt P» 01</td><td>rt r- kp οι</td><td>ot ut kP OI</td><td>Ot F kP 01</td><td>o rt kp OI</td><td>F F Ut OI</td><td>rt ko F rt</td><td>kO OI F 01</td><td>rt OI F OI</td><td>co rt rt 01</td><td>ot oo Oí OI</td><td>rt rt rt 01</td><td>co p* rt OI</td><td>rt 0» rt OI</td><td>co rt rt OI</td><td>kO rt rt 01</td><td>co rt rt OI</td>

<td>1 o 2 58</td><td>rt á a</td><td>rt! rt rt</td><td> 1</td><td>rt a a</td><td>rt fe H H</td><td>O kO kO o ot rt</td><td>OI 8</td><td>ko I</td><td>s</td><td>rt rt W</td><td>rt F 44 S Ut rt 0</td><td>« rt</td><td>Q m rt</td><td>UJ</td><td></td><td> 1</td><td>fe fe fe</td><td></td><td>ω</td><td> !</td><td>O rt i</td><td>F Ut 44 8 01 0</td><td>Ot rt F O O</td><td></td><td>rt rt 3 U) 1</td>

<td rowspan="2">si⁵ j si 0 n</td><td rowspan="2">rt O O) 8</td><td rowspan="2">rt O OI 8</td><td rowspan="2">rt O</td><td rowspan="2">rt O OJ 8</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td rowspan="2">rt O</td><td rowspan="2">rt O</td><td rowspan="2">rt O rt</td><td rowspan="2">rt O</td><td rowspan="2">rt O rt 8</td><td rowspan="2">rt O rt 8</td><td rowspan="2">rt O</td><td>rt</td><td>rt</td><td>rt</td>

<td>O OJ 8</td><td>O</td><td>O</td><td>O rt</td><td>O rt 8</td><td>O</td><td>O M</td><td>O rt</td><td>O</td><td>O rt 8</td><td>O</td><td>O</td><td>O</td><td>O</td>

<td>Peso de la sonda</td><td>00 F C—</td><td>Γ- ΟΟ kp</td><td>OI rt kP</td><td>rt OJ kP</td><td>rt O kP</td><td>OI co ut</td><td>kp kO U5</td><td>rt F F</td><td>rt co rt</td><td>kD Ut rt</td><td>00 r- oi</td><td>kO CO rt</td><td>Ot Ut rt</td><td>0- U1 rt</td><td>kO rt rt</td><td>Ut rt rt</td><td>O rt rt</td><td>0* O rt</td><td>O O rt</td><td>F oo</td><td>F kP</td><td>rt ut</td><td>OI F</td><td>Ot rt</td><td>co rt</td>

<td>1 CQ s 1 8 £</td><td>rt 9 kP Ut s</td><td></td><td>I</td><td>CO CO ot rt F ko 8</td><td>rt</td><td> 1</td><td>F Oí fe a</td><td></td><td>s 8</td><td>W</td><td>rt 0</td><td> !</td><td></td><td>rt i</td><td>í</td><td>rt</td><td>g a a</td><td>OI w</td><td> §</td><td></td><td>rt</td><td>F a a</td><td>a 0</td><td>a ut i</td><td>i</td>

<td rowspan="2">¿1 U rt rt S £ 5 J ffl rt o n</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td rowspan="2">rt O rt 8</td><td>rt</td><td>rt</td><td>rt</td><td rowspan="2">rt O 0</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td rowspan="2">rt O rt 8</td><td rowspan="2">rt O §</td><td rowspan="2">rt O y</td><td rowspan="2">rt O s</td>

<td>O OI 8</td><td>O Oí 8</td><td>O OI 8</td><td>O 0</td><td>O OI 8</td><td>O</td><td>O OI 8</td><td>O</td><td>O</td><td>O rt</td><td>O rt 8</td><td>O</td><td>O rt</td><td>O rt 8</td><td>O rt 8</td><td>O rt 8</td><td>O</td><td>O</td><td>O</td>

<td>Peso de la sonda</td><td>ut OI co kP</td><td>F OI CO kP</td><td>ot kP kp kp</td><td>rt O kp kO</td><td>rt co in kp</td><td>rt rt ut kP</td><td>rt CO F kO</td><td>o 00 F kP</td><td>co Ut F kO</td><td>rt rt F kp</td><td>OI rt F kp</td><td>ot ot rt kO</td><td>Ot Ot rt kp</td><td>ko F rt kO</td><td>kO rt rt kp</td><td>rt CO Oí kp</td><td>00 r- Ol kO</td><td>rt Ut 01 kp</td><td>kP rt OI kP</td><td>rt C0 rt kp</td><td>Ot Γ* rt kP</td><td>ut kP rt kP</td><td>F rt rt kP</td><td>o o rt kP</td><td>co r- © kP</td>

<td>Gen Co- expresado</td><td>O rt</td><td>rt r- F rt F</td><td> 8</td><td>rt §</td><td></td><td>rt</td><td>rt e H u</td><td>33 9 fe fe fe</td><td>rt 1</td><td>8 w w</td><td>rt</td><td>S H</td><td>rt</td><td>rt 0 H N</td><td>o a kO a w</td><td>3 rt fe</td><td>ut a s</td><td>o a g</td><td></td><td>g</td><td>O r* o kO F kP 8</td><td>Ut 8 w 0</td><td>I</td><td></td><td>s Ü</td>

<td>si si</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td>

ιη

O LD

Η Η

I

136

<img file="MX366164B_D0032.tif" />

<td>Gen de siembra</td><td>MYBL2</td><td>MYBL2</td><td>MYBL2</td><td> 1</td><td> 1</td><td></td><td> 1</td><td></td><td>a</td><td></td><td> 1</td><td> 1</td><td>CJ i</td><td>a</td><td>CJ i</td><td>Cl i</td><td> 1</td><td> 1</td><td>i</td><td> 1</td><td> 3</td><td>i</td><td> 1</td><td> 1</td>

<td>Peso de la sonda</td><td>O b o Cl</td><td>O b o CJ</td><td>rd O O Cd</td><td>b on co rd</td><td>Cl un co rd</td><td>o b P rd</td><td>tn b b rd</td><td>Cl en b rd</td><td>b o b rd</td><td>CJ P tn rd</td><td>on rd tí rd</td><td>en on en rd</td><td>o tí re rd</td><td>00 b Cl rd</td><td>b un CJ rd</td><td>ω CJ CJ rd</td><td>en 00 rd rd</td><td>en 00 rd rd</td><td>O CO rd rd</td><td>CO P rd rd</td><td>co P rd rd</td><td>rd on on</td><td>b en on</td><td>un un 00</td>

<td>i a 8 $8</td><td>i</td><td>en b rd U-l 8 on U</td><td>i</td><td></td><td>O un Md 8 on U</td><td>tí 0</td><td>Éh</td><td> 1</td><td>P O f*&gt; CO Cl P</td><td>a g</td><td>a i</td><td>tn tí H O</td><td>J H</td><td></td><td> 1</td><td>O un i</td><td> !</td><td> 1</td><td>U Cl tí B</td><td>rd ^0</td><td>to</td><td>rd u w</td><td></td><td>i</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>Gen de siembra</td><td>O Cd §</td><td> 1</td><td> 1</td><td>i</td><td>i</td><td> 1</td><td> 1</td><td> 1</td><td> !</td><td>i</td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>a</td><td> 1</td><td>i</td><td>i</td><td> 1</td><td> !</td><td> 1</td><td> 1</td><td>i</td><td>i</td>

<td>Peso de la sonda</td><td>CJ rd</td><td>co o CJ CJ rd</td><td>00 o cd es rd</td><td>co o CJ cd rd</td><td>o on rd Cd rd</td><td>Cl en o CJ rd</td><td>tn rd O CJ rd</td><td>tn rd on rd rd</td><td>tí P P rd rd</td><td>tí P P rd rd</td><td>b tn en rd rd</td><td>CJ b o rd rd</td><td>o rd O rd rd</td><td>o CJ P o rd</td><td>rd un b O rd</td><td>co CJ b o rd</td><td>on co CJ o rd</td><td>un 00 Cl o rd</td><td>tí rd Cl O rd</td><td>un on rd O rd</td><td>en o rd O rd</td><td>tí on o o rd</td><td>on p o o rd</td><td>rd b On on</td>

<td>1 § lé 1</td><td> 9</td><td></td><td>un tí</td><td> !</td><td>§ ω w</td><td>CJ b</td><td>tí co Pm B</td><td>c tí 1</td><td>rd 1</td><td>a S «1</td><td>rd tí e</td><td>rd tí 3</td><td></td><td>C^</td><td>i</td><td></td><td> 5</td><td> !</td><td>a H</td><td>P tí a</td><td>O O rd IW U 0 on U</td><td>tí</td><td>m</td><td>a</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>8 S a 1 rs</td><td>O</td><td>O</td><td>O OI</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O CJ</td><td>O</td><td>O</td><td>O</td><td>O Cl 8</td><td>O</td><td>O</td><td>O CJ</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O §</td>

<td>8 - 1 § 0 ti CU rd</td><td>P tí O b</td><td>rd en O b</td><td>un rd O b</td><td>on on on un</td><td>en on on un</td><td>on co on un</td><td>rd P on tn</td><td>rd P on tn</td><td>tn rd On tn</td><td>tn rd on tn</td><td>tn rd on un</td><td>CJ rd On tn</td><td>en on CO un</td><td>00 00 CO un</td><td>en rd 00 tn</td><td>Cl tí P un</td><td>00 CJ P un</td><td>rd P b un</td><td>en tí b un</td><td>un b un un</td><td>rd en un un</td><td>un CJ un un</td><td>rd On tí un</td><td>rd on tí un</td>

<td>3 n $ 8 §*</td><td>fe</td><td> «</td><td>P co cd O O rd Q cj Q rd hd rd</td><td>o</td><td></td><td>en 1</td><td>co a tí</td><td></td><td>u rd rn rd i tí</td><td>i</td><td>g H</td><td>rd tí CJ tí</td><td>p tí Cl tí</td><td>tí b</td><td>rd CO Md s rd u</td><td>a H</td><td>rd b O on Cl P</td><td>B %</td><td>tí</td><td>i</td><td>b</td><td>o en h</td><td></td><td></td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

ι

ΪΝ

137

<td>4 Ü α</td><td>MYBL2</td><td> 1</td><td> 1</td><td>MYBL2</td><td>MYBL2</td><td> 1</td><td>MXBL2</td><td> 1</td><td>a</td><td></td><td></td><td></td><td> 1</td><td> 1</td><td> 1</td><td> 1</td><td>a</td><td>a</td><td>MYBL2</td><td>a</td><td>i</td><td> 1</td><td> 1</td><td></td><td> 1</td>

<td rowspan="2"> •3 8 1</td><td>O</td><td>fO</td><td>OJ</td><td>rd</td><td> &gt;</td><td>CO</td><td>ro</td><td>m</td><td>o</td><td>co</td><td>OJ</td><td>σι</td><td> 04</td><td>«a*</td><td>r-</td><td>m</td><td> 5»·</td><td> 0}</td><td>o&gt;</td><td rowspan="2">*· σι</td><td>s</td><td> 00</td><td>co</td><td> 04</td><td>rd</td>

<td>r·</td><td>r-</td><td>co</td><td>CO</td><td>co</td><td>un</td><td>m</td><td></td><td></td><td> *·</td><td></td><td>ro</td><td>ro</td><td>OJ</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td></td><td></td><td></td><td></td><td></td>

<td>Φ tí δ 0 Η β</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>δ</td><td>in o rd</td><td></td><td></td><td></td><td>a</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">OJ</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2">a s 0</td><td></td><td></td>

<td>ί</td><td>8 O rd u</td><td>a H</td><td>0 É 0</td><td></td><td></td><td>w</td><td>Éu</td><td>i o</td><td>g</td><td>co ro</td><td>w</td><td>I</td><td></td><td>ΙΠ i</td><td>rd 1</td><td>4 2 H</td><td> 1</td><td>s §</td><td>g</td><td> 1</td><td>0 2 a</td><td>O 2 a</td><td></td>

<td> 4</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>s&gt;</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td> — _βΊ</td><td></td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>a</td><td>a</td><td>a</td><td>i</td><td>a</td><td></td><td>i</td><td> 1</td><td>i</td><td> 3</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>q</td><td>i</td>

<td>φ *Η 0 α</td><td> 1</td><td>i</td><td> 1</td><td> !</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>g</td><td> 1</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td> 1</td><td>i</td><td>i</td>

<td>Λ *</td><td> &lt;4*</td><td>CO</td><td> 04</td><td>σι</td><td>r-</td><td>σι</td><td>OJ</td><td>σι</td><td>OJ</td><td>ro</td><td>en</td><td>σι</td><td>rd</td><td></td><td>co</td><td>rd</td><td>ro</td><td>o</td><td>en</td><td></td><td>M·</td><td>rd</td><td>co</td><td>OJ</td><td>un</td>

<td> 0 ^Η 3</td><td>co</td><td>Γ0</td><td> 04</td><td>r*</td><td>co</td><td>co</td><td>un</td><td>m</td><td>s</td><td>S</td><td>OJ</td><td> 04</td><td>rd</td><td>o</td><td>ω</td><td> £</td><td>co</td><td>un</td><td> ?</td><td>ro</td><td>O</td><td>S</td><td>co</td><td> 00</td><td></td>

<td>3 ® ο w Ό η</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>co</td>

<td> ·§</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>σι σι</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td rowspan="2"> 9</td><td>ro</td><td></td><td></td>

<td>η</td><td> 03</td><td></td><td>fi</td><td rowspan="2">m</td><td></td><td rowspan="2">c^</td><td></td><td></td><td>rd</td><td></td><td> £0</td><td></td><td>o</td><td></td><td rowspan="2">á</td><td></td><td>►q</td><td></td><td></td><td></td><td></td><td>Md</td><td></td><td>U</td>

<td> §¿1</td><td> 1</td><td>i</td><td> 1</td><td>i</td><td>i</td><td>i</td><td>i</td><td>i</td><td>H</td><td></td><td>i</td><td> 1</td><td>g</td><td></td><td>o 0 a</td><td>H</td><td> 1</td><td>i</td><td>rd Ü</td><td>b Vt· rd U</td><td>i</td><td> 0</td>

<td>•d</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>s#</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td> 3</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>i</td><td>O OJ</td><td>O OJ</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O OJ</td><td>O Oí</td><td>O OJ</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O OJ</td><td>O 04</td><td>O</td><td>O OJ</td><td>O 04</td><td>O</td>

<td>8 -rl Ο α</td><td> 8</td><td> 8</td><td>y</td><td>y</td><td> §</td><td> 0</td><td> 0</td><td> §</td><td> 8</td><td> 8</td><td> 8</td><td> §</td><td> §</td><td> 0</td><td> 0</td><td> §</td><td>s</td><td> 0</td><td>y</td><td> 8</td><td> 8</td><td> 0</td><td> 8</td><td> 8</td><td>i</td>

<td rowspan="2">jo de sonda</td><td>rd (Ji</td><td>rd σ&gt;</td><td>r-</td><td>«4« o»</td><td>Γ-</td><td>σι ro</td><td>en ro</td><td>m ro</td><td>00 co</td><td>rd σι</td><td>rd CO</td><td>en o~</td><td>m r~-</td><td>rd</td><td>co co</td><td>co ro</td><td>rd</td><td>en σι</td><td>00 o~</td><td>co στ</td><td>in 00</td><td>ro o*</td><td>ro ro</td><td>00 o</td><td>co OJ</td>

<td>ID</td><td>un</td><td>un</td><td>m</td><td>m</td><td>in</td><td>en</td><td>en</td><td>un</td><td>un</td><td>en</td><td>en</td><td>en</td><td>in</td><td>un</td><td>un</td><td>en</td><td>en</td><td>LA</td><td>M·</td><td></td><td>-Ψ</td><td> *4·</td><td>’í'</td><td></td>

<td>Φ tí 0 rd</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>i</td><td></td><td></td><td></td><td></td><td></td><td>co r-</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>ro</td><td></td><td></td><td></td><td></td><td>OJ</td><td></td><td></td><td></td>

<td>o</td><td>CO</td><td>_t</td><td></td><td></td><td></td><td>OJ</td><td></td><td>in</td><td>s</td><td>rd</td><td></td><td></td><td>o</td><td rowspan="2">0 co a H</td><td> 2</td><td></td><td>cw</td><td></td><td></td><td></td><td></td><td>Oí</td><td>d</td><td></td><td></td>

<td> ¿4</td><td></td><td> 2</td><td>o a</td><td>g</td><td> £ 6</td><td></td><td> ¡</td><td> 55</td><td>ti 0 0</td><td>rj</td><td>e H O</td><td>i</td><td> §</td><td>Θ</td><td> 1</td><td>O 0» rd υ</td><td>Ϊ</td><td> §</td><td>O 00 U</td><td> §</td><td>8 rd u</td><td>s</td><td>i</td><td></td>

<td>s|</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>s #</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

ο ιη

Γ—( Γ-1

I

138

<td>Gen de siembra</td><td>MYBL2</td><td> 1</td><td></td><td>s e¡</td><td></td><td></td><td></td><td></td><td></td><td></td><td>s &amp;</td><td></td><td></td><td>g &amp;</td><td>g &amp;</td><td>g 9</td><td>g</td><td></td><td>g</td><td>g</td><td>M</td><td>M</td><td></td><td></td><td>g</td>

<td>&lt;8 § 1 Φ flj o fe rd CQ</td><td>σι rd</td><td>r- rd</td><td>rd rd</td><td>rd rd</td><td>o rd</td><td>o-</td><td>kD</td><td> &lt;3*</td><td>-Φ</td><td>s*</td><td></td><td>rq</td><td>rq</td><td>rq</td><td>OI</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>σι rq</td><td>00 rq</td><td>kO rq</td><td>kO rq</td><td>kD rq</td>

<td>Ί co 0 i* $5</td><td>ui a fe en</td><td>á y</td><td>p</td><td>g 8</td><td>H</td><td> !</td><td>H</td><td>a</td><td>o- É</td><td>i</td><td>H</td><td>m rd H</td><td>rd o rd O</td><td>_l</td><td>9 rd rd i</td><td>_l</td><td>rd fe a</td><td>rd i</td><td></td><td>O» É</td><td>Ul υ</td><td>§ a</td><td>s a</td><td>g O</td><td>fe fe a</td>

<td> 3|</td><td>rd</td><td>rd</td><td rowspan="2">rd 1</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>OI</td><td> 01</td><td>OI</td><td> 01</td><td>fS</td><td> 03</td>

<td>&lt;8 co si O a</td><td>i</td><td> 1</td><td> 1</td><td></td><td></td><td>i</td><td></td><td>i</td><td> 1</td><td></td><td> 1</td><td>i</td><td>i</td><td> 1</td><td> 1</td><td></td><td>a</td><td></td><td> 1</td><td></td><td> §</td><td> !</td><td> 1</td><td> 1</td>

<td>Peso de la sonda</td><td>o 03 o- kD</td><td>Ul rd Ul kO</td><td>rq rd kD</td><td>OI o ”3· kD</td><td>. fS co rq kO</td><td>o kü 01 kD</td><td>OI rd rq kX&gt;</td><td>Ul o o» kO</td><td>kO OI o kD</td><td>o 01 o kD</td><td>o rd O kO</td><td>kO 01 oo U)</td><td>kO σι oo Ul</td><td>o «3¹00 Ul</td><td>00 rq 00 Ul</td><td>σι Ul kD Ul</td><td>rq 01 Ul Ul</td><td>rd r Ul Ul</td><td>r- rq rq Ul</td><td>kD co Ol Ul</td><td>kD rd Ul</td><td>rq OI rd Ul</td><td>co kD O IA</td><td>rd kD O Ul</td><td>o m σι</td>

<td>1 Jií</td><td>H</td><td>ιχ&gt; N fe W</td><td>rd</td><td> 1</td><td></td><td>rd</td><td>o Ul rq r- 01</td><td>rd ü</td><td>Ul</td><td>01 Md s rd υ</td><td>rj</td><td>rq rd</td><td>Ul</td><td>O co υ</td><td></td><td>o rd</td><td>Ul rq rd</td><td>S* rd</td><td>fe</td><td> 1</td><td>H</td><td>fe y</td><td></td><td> ¡</td><td>a 9</td>

<td>Id del l Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>Gen de siembra</td><td>O</td><td>O fS y</td><td>O 0</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O 0</td><td>O §</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O</td><td>O y</td><td>O</td><td>O</td><td>O y</td><td>O</td><td>O</td><td>O 0</td><td>O</td><td>O 0</td>

<td>Peso de la sonda</td><td>r— σι</td><td>Ul o- &lt;3·</td><td>rd Ul Φ</td><td>en co ω</td><td>01 01 Cd «3&lt;</td><td>Γ* σι OI</td><td>O» r» 01</td><td>rd rd Ol</td><td>tn Ul rd &lt;3·</td><td>rq rd rd</td><td>rq kD O</td><td>Ch Ul o</td><td>rq rd σι rq</td><td>σι *3* &gt; rq</td><td>rd ω kD rq</td><td>ui kD kD rq</td><td>co rq kD rq</td><td>σι co Ul rq</td><td>rq &gt; Ul rq</td><td>rd Ul Ul rq</td><td>rd Ul Ul rq</td><td>rd Ul Ul rq</td><td>rd *&lt; Ul rq</td><td>kO rs M* rq</td><td>σι 01 rq rq</td>

<td> 1</td><td>rd y 8</td><td> 5</td><td>i fe</td><td></td><td></td><td></td><td>ιη</td><td></td><td>g</td><td>Ol kO m 8 8</td><td> 1</td><td>i</td><td>00 i</td><td>OI rd fe</td><td>rd i</td><td>o O- M-l &amp; OI U</td><td>01 8 a</td><td></td><td>O ω</td><td> 1</td><td>fe OI fe 2</td><td> !</td><td>υ 03 fe a</td><td>a H i</td><td></td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

ιη ι

139

<td>Gen de siembra</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>s &amp;</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>TPX2</td><td>g</td><td>g</td><td> 1</td><td>g</td><td>g</td>

<td>Peso de la sonda</td><td>rn m</td><td>rd en</td><td>rd m</td><td>O m</td><td>Γ* d</td><td>Γ- d</td><td>so d</td><td>so d</td><td>un d</td><td>O d</td><td>os H</td><td>co H</td><td>Γ- Η</td><td>SO H</td><td>US H</td><td>un H</td><td>H</td><td>m H</td><td>rn H</td><td>a</td><td>o H</td><td>so</td><td>us</td><td>rn</td><td>d</td>

<td>§ Q s &amp;</td><td>d £ É*«</td><td>•Φ rd b B</td><td>rd 0</td><td>M</td><td>US a b W</td><td>H U</td><td>H 9 PQ</td><td> 1</td><td>i</td><td> 1</td><td>_i</td><td>a 1 PQ</td><td>O d</td><td>un b 8</td><td>á d b B</td><td> 9 8 8</td><td>_g</td><td>H d</td><td></td><td>s</td><td>Q</td><td>rn £ B</td><td>H !</td><td>d</td><td>H</td>

<td>Id del Apilado</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td rowspan="2">d</td><td rowspan="2">d</td><td rowspan="2">d</td><td rowspan="2">d</td><td rowspan="2">d</td><td rowspan="2">d</td><td rowspan="2">d</td><td rowspan="2">d</td><td rowspan="2">d</td><td rowspan="2">d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td><td>d</td>

<td>Gen de siembra</td><td> !</td><td> 1</td><td> !</td><td></td><td> 1</td><td>i</td><td> !</td><td> 1</td><td> 1</td><td>i</td><td> 1</td><td></td><td> 1</td><td></td><td></td>

<td>Peso de la sonda</td><td>H O OS •Φ</td><td>rd O OS xP</td><td>Γ- ΟΟ 00 •Φ</td><td>rd un 00 Φ</td><td>c* Φ co Φ</td><td>Γ- ©· 00</td><td>OS o 00 xP</td><td>o d Γ- xp</td><td>o d r- xp</td><td>Γ- Η r- xp</td><td>H H Γ- Φ</td><td>O os so xp</td><td>H SO so</td><td>os d so Φ</td><td>xp os H ’Φ</td><td>o so rn xp</td><td>so rn rn «P</td><td>00 o m xp</td><td>m ω d XP</td><td>so Γ- d χρ</td><td>H H H xp</td><td>f- o H Φ</td><td>xP 00 os rn</td><td>Γ- Γ* os rn</td><td>en Γ- όη en</td>

<td>g¿Í</td><td>8 H</td><td> 1</td><td></td><td>d</td><td>D</td><td>US H</td><td>g</td><td>_l</td><td> !</td><td>H un Md &amp; Γ- Η U</td><td></td><td>_l</td><td>g</td><td>b os H d H</td><td>H H</td><td>g</td><td>Γ- Η H Md 8 OS u</td><td></td><td>PQ ω</td><td>i ω</td><td> 1 1</td><td>b co</td><td>H</td><td></td><td> 1</td>

<td>Id del Apilado</td><td>i—1</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td>

<td>8 1 3 ’ 0 Q</td><td>O d §</td><td>O y</td><td>O d 8</td><td>O d 8</td><td>O</td><td>O</td><td>O 0</td><td>O</td><td>O d</td><td>O</td><td>O d</td><td>O</td><td>O</td><td>O</td><td>O d 8</td><td>O 0</td><td>O §</td><td>O</td><td>O d 8</td><td>O d 8</td><td>O</td><td>O d 8</td><td>o d 8</td><td>o d 8</td><td>O d 8</td>

<td>8 &lt;« 1 o β O á! Λ</td><td>LA OS rn en</td><td>rd xí* rn H</td><td>o *φ m (*S</td><td>Γ- Η (*·) H</td><td>Γ- Η H H</td><td>H H H H</td><td>os H d f*S</td><td>XP Os H CO</td><td>os o H rn</td><td>xP co OS d</td><td>so H OS d</td><td>OS o co d</td><td>O U1 r* d</td><td>H un so d</td><td>H •Φ SO d</td><td>xp m un d</td><td>os os •Φ d</td><td>Γ- όη Φ d</td><td>©· rn Φ d</td><td>m H f*S d</td><td>00 US d d</td><td>d rn d d</td><td>os os H d</td><td>XP Γ- Η d</td><td>o rn H d</td>

<td>1 n 8 m</td><td> 1</td><td>C- b B</td><td>os H</td><td></td><td>H</td><td>l</td><td>H</td><td>Si Γ- Η i</td><td>a gi</td><td>Q</td><td>g 3</td><td>d H</td><td>fe g</td><td>i¡</td><td>os xp xP &lt;p un H §</td><td>a s B</td><td> 1</td><td>0 H i</td><td></td><td></td><td>b</td><td>co b a</td><td>i</td><td>g</td><td></td>

<td>as·</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td><td>H</td>

ο ιη γΗ «Η

I

0

<td> % 11</td><td></td><td></td><td></td><td>s g¡</td>

<td>Peso de la sonda</td><td>Cí</td><td>Cí</td><td>Cí</td><td>rt</td>

<td>$ 0 j·</td><td> 1</td><td> 1</td><td>i</td><td>rt</td>

<td>3 i 5 %</td><td>Cí</td><td>Cí</td><td>Cí</td><td>Cí</td>

<td>Gen de siembra</td><td> 1</td><td> 1</td><td></td><td></td>

<td>Peso de la sonda</td><td>00 to co to</td><td>to to 00 to</td><td></td><td></td>

<td>1 Q 2 sá?</td><td>to a&gt; to o &lt;n to</td><td>rt</td><td></td><td></td>

<td>d sa*</td><td>rt</td><td>rt</td><td></td><td></td>

<td>© 1 O Q</td><td>O Cí 8</td><td></td><td></td><td></td>

<td>|- Peso de la sonda</td><td>o 00 o Cí</td><td></td><td></td><td></td>

<td>1 » &amp; lis ?</td><td>fe to fe §</td><td></td><td></td><td></td>

<td>d sa·</td><td>rt</td><td></td><td></td><td></td>

un o m i

<img file="MX366164B_D0033.tif" />

141

Tabla 11

<td>© nJ Ό k «1 © -H O n</td><td>GADD45B</td><td>GADD45B</td><td>GADD4 5B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>ZFP36</td><td>ZFP36</td><td>LO n fe fe N</td><td>LO fA fe fe N</td><td>LO (A fe fe N</td><td>ZFP36</td><td>ZFP36</td><td>ZFP36</td><td>ZFP36</td><td>LO fA fe fe tsl</td><td>LO fA fe fe N</td><td>ZFP36</td><td>ZFP36</td>

<td>Peso de la sonda</td><td>A¹</td><td> &lt;4*</td><td>fA</td><td>rA</td><td>CS</td><td>es</td><td>es</td><td>es</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>(A LA</td><td>en A⁴</td><td> 29</td><td> 26</td><td> 24</td><td>A· es</td><td>O es</td>

<td>Gen Co- expresado</td><td>ZFP36</td><td>SOCS3</td><td>RHOB</td><td>BHLHE40</td><td>FOS</td><td>FOSL2</td><td>es O H CQ</td><td>(A</td><td>FOSB</td><td>IRFl</td><td>F0SL2</td><td>HBEGF</td><td>O A* fe s fe fe</td><td>HBEGF</td><td>fA A fe 2</td><td>BHLHE4 0</td><td>CSRNPl</td><td>ZFP36</td><td> 1</td><td>FOS</td><td>BHLHE40</td><td>BTG2</td><td>FOSB</td>

<td>Id del Apilado</td><td>fA</td><td>&lt;A</td><td>fA</td><td>fA</td><td>fA</td><td>(A</td><td>(A</td><td>fA</td><td>fA</td><td>fA</td><td>rd</td><td>rd</td><td>rd</td><td>es</td><td>es</td><td>es</td><td>fA</td><td>fA</td><td>fA</td><td>fA</td><td>fA</td><td>fA</td><td>ΓΑ</td>

<td>5 (0 «i © «H O »</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>CO o fe</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>co O fe</td><td>en O fe</td><td>FOS</td><td>FOS</td><td>CO O fe</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>CO g</td>

<td>Peso de la sonda</td><td>A* rd</td><td>a· rd</td><td>fA rd</td><td>fA rd</td><td>σι</td><td>r-</td><td>r-</td><td>LO</td><td>LO</td><td>IA</td><td>LA</td><td>LA</td><td>LA</td><td>A*</td><td>A*</td><td>A*</td><td>fA</td><td>es</td><td>rd</td><td>A* es</td><td>es es</td><td>O es</td><td>σι rd</td>

<td>Gen Co- expresado</td><td>FOS</td><td>CS O Pl CQ</td><td>CSRNPl</td><td>ZFP36</td><td>m</td><td>&lt;A s</td><td>FOSB</td><td>SIK1</td><td>BHLHE40</td><td>RHOB</td><td>fe fe fe H H</td><td>LO fe a</td><td>rd u s</td><td>rd C §</td><td>EGRl</td><td>NR4A2</td><td>GADD45B</td><td>SOCS3</td><td>NFKBIZ</td><td>FOS</td><td>FOSB</td><td>EGRl</td><td>NR4A1</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>fS</td><td>es</td><td>es</td><td>es</td>

<td>Gen de siembra</td><td>rd &amp; CO g</td><td>DUSPl</td><td>DUSPl</td><td>rd Oí CO g</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>rd fe CO g</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td>

<td>Peso de la sonda</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>H</td><td>CO</td><td>t-</td><td>c-</td><td>lfl</td><td>Lfl</td><td>lfl</td><td>A⁴</td>

<td>Gen Co- expresado</td><td>, NNT</td><td>RNF180</td><td>¡ PCDH18</td><td>RNF180</td><td>' DUSPl</td><td>PCDH18</td><td>¡ ACTB</td><td>: RHOB</td><td>DUSPl</td><td>; ACTB</td><td>^! DUSPl</td><td>CRTAP</td><td>RNF180</td><td>DUSPl</td><td>, CRTAP</td><td>fe</td><td>DUSPl</td><td>NR4A1</td><td>FOS</td><td>EGRl</td><td>BTG2</td><td>FOSB</td><td>_!</td>

<td>Id del Apilado</td><td>rd</td><td>rd</td><td>rd</td><td>CS</td><td>es</td><td>CS</td><td>fA</td><td>fA</td><td>ÍA</td><td>A*</td><td>A*</td><td>A*</td><td>LA</td><td>LA</td><td>LA</td><td>IA</td><td>LO</td><td>LO</td><td>LO</td><td>LO</td><td>LO</td><td>LO</td><td>LO</td>

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O r4 tn rd ‘ '•S

142

<td>0) rt Ό M J Φ id O n</td><td>ZFP36</td><td>ZFP36</td><td>ZFP36</td><td>so ΓΏ CU fe N</td><td>ZFP36</td><td>ZFP36</td><td>so en cu fe N</td><td>ZFP36</td><td>ZFP36</td><td>SO (Ό fe fe N</td><td>ZFP36</td><td>SO m cu fe co</td><td>ZFP36</td><td>ZFP36</td><td>SO m cu fe N</td><td>ZFP36</td><td>ZFP36</td><td>so m fe fe N</td><td>so m cu fe N</td><td>ZFP36</td><td>ZFP36</td><td>ZFP36</td><td>ZFP36</td><td>so m cu fe N</td><td>ZFP36</td>

<td>Peso de la sonda</td><td>00 rd</td><td>00 rd</td><td>SO rd</td><td>SO rd</td><td>tn rd</td><td>tn rd</td><td> 10</td><td>en</td><td> 00</td><td> 00</td><td> 00</td><td> 00</td><td>r-</td><td>Γ-</td><td>Γ*</td><td>SO</td><td>so</td><td>SO</td><td>tn</td><td>tn</td><td>tn</td><td>*F</td><td>sF</td><td></td><td>m</td>

<td>0 Ό flt Q Φ 8 ό ΐ O O Φ</td><td>NR4A3</td><td>SOCS3</td><td>EGRl</td><td>RHOB</td><td>FOSL2</td><td>rd «¡f</td><td>oa tn Q § o</td><td>MYADM</td><td>so fe á</td><td>CYR61</td><td>EGR3</td><td>EMP1</td><td>LMNA</td><td>fe H</td><td>NR4A2</td><td>MCLl</td><td>SIK1</td><td>ATF3</td><td>CEBPD</td><td>IER3</td><td>CD fe fe H</td><td>fe fe</td><td>IRFl</td><td>RNF122</td><td>fe fe W</td>

<td>Id del Apilado</td><td>m</td><td>m</td><td>m</td><td>en</td><td>m</td><td>en</td><td>m</td><td>Ό</td><td>m</td><td></td><td>m</td><td>m</td><td>ΓΏ</td><td> &lt;*)</td><td>en</td><td>en</td><td>m</td><td>en</td><td>en</td><td>en</td><td>en</td><td>en</td><td>en</td><td>rn</td><td>en</td>

<td>Gen de siembra</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>FOS</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td>

<td>Peso de la sonda</td><td>00 rd</td><td>CD rd</td><td>rd rd</td><td>O rd</td><td>oo</td><td> 00</td><td>r-</td><td>so</td><td>so</td><td>so</td><td>so</td><td>so</td><td>in</td><td>&lt;F</td><td>m</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>rd</td><td>r-</td><td>r-</td><td>Γ-</td><td>^F</td><td>en</td>

<td>Gen Co- expresado</td><td>CD 0 03</td><td>ZFP36</td><td>CSRNPl</td><td>CYR61</td><td>DÜSPl</td><td>en fe s</td><td>IER2</td><td>RHOB</td><td>TIPARP</td><td>CD ’F</td><td></td><td>ffl</td><td>EGR3</td><td>NR4A3</td><td>so fe á</td><td>PPP1R15A</td><td>NEDD9</td><td>KLF4</td><td>CD fe O fe</td><td>MCLl</td><td>rd fe s fe</td><td>BHLHE40</td><td>SOCS3</td><td>m &lt;F fe</td><td>FOSL2</td>

<td>Id del Apilado</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>CD</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td>

<td>V flt Ό h al φ -H O a</td><td>DUSP1</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>DUSPl</td><td>rd fe CO o Q</td><td>rd fe CO o o</td><td>EGRl</td><td>EGRl</td><td>EGRl</td><td>rd fe O ω</td><td>rd fe O fe</td><td>rd fe O w</td><td>rd fe O w</td><td>rd fe O fe</td><td>rd fe O w</td><td>rd fe U fe</td><td>EGRl</td><td>EGRl</td><td>EGRl</td><td>rd fe O fe</td><td>rd fe O fe</td><td>EGRl</td><td> EGRl</td>

<td>Peso de la sonda</td><td>m</td><td>m</td><td> (*»</td><td>CD</td><td>CD</td><td>CD</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>rd</td><td>tn en</td><td>O en</td><td>tn CD</td><td>m CD</td><td>CD CD</td>

<td>Gen Co- expresado</td><td>CD M· fe Z</td><td>TIPARP</td><td>CYR61</td><td>ATF3</td><td>RHOB</td><td>NEDD9</td><td>MOLI</td><td>rd O fe á</td><td>JUNB</td><td>TIPARP</td><td>BTG2</td><td>JUNB</td><td>BTG2</td><td>rd fe O ω</td><td>’F fe fe</td><td>FOSB</td><td>EGRl</td><td>FOSB</td><td>CSRNPl</td><td>EGRl</td><td>rd fe O fe</td><td>W g</td><td>NR4A1</td><td>FOSB</td><td>BTG2</td>

<td>Id del Apilado</td><td>so</td><td>SO</td><td>so</td><td>so</td><td>so</td><td>so</td><td>SO</td><td>so</td><td>rd</td><td>rd</td><td>rd</td><td>CD</td><td>CD</td><td>CD</td><td>en</td><td>en</td><td>m</td><td></td><td></td><td></td><td>tn</td><td>tn</td><td>tn</td><td>in</td><td>tn</td>

in

LD ic

143

<td>© © Ό M «i © rt 0 Q</td><td>to to fe fe N</td><td>ZFP36</td><td>ZFP36</td><td>to to fe fe N</td><td>ZFP36</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Paso de la sonda</td><td>Cí</td><td> 01</td><td>Oí</td><td>OI</td><td>rt</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Gen Co- expresado</td><td>ERRFI1</td><td>SLC25A25</td><td>CDKN1A</td><td>EGR2</td><td>P fe a</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Id del Apilado</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>Gen de siembra</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>a in &lt;3· Q §</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td><td>GADD45B</td>

<td>Peso de la sonda</td><td>to</td><td>to</td><td>to</td><td>to</td><td>Oí</td><td>rt</td><td>OI</td><td>Oí</td><td>OI</td><td>Oí</td><td>Cí</td><td>Cí</td><td>Oí</td><td>Oí</td><td>Oí</td><td>OI</td><td>rt</td><td>rt</td><td>rt</td><td> «3*</td><td></td><td></td>

<td>Gen Co- expresado</td><td>GADD45B</td><td>RNF122</td><td>KLF10</td><td>CSRNPl</td><td>SLC2A3</td><td>to to fe fe N</td><td>FOSB</td><td>NR4A1</td><td>FOS</td><td>GADD45B</td><td>BTG2</td><td>to * fe Z</td><td>a</td><td>EGRl</td><td>CSRNPl</td><td>ZFP36</td><td>RHOB</td><td>EGR3</td><td>ATF3</td><td>GADD45B</td><td>JUNB</td><td>CSRNPl</td>

<td>Id del Apilado</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>rt</td><td>OJ</td><td>OI</td><td>Cí</td><td>Cí</td><td>Cí</td><td>Cí</td><td>Cí</td><td>Cí</td><td>OI</td><td> 01</td><td>Oí</td><td>Cí</td><td> 01</td><td>to</td><td>to</td><td>to</td>

<td>Gen de siembra</td><td>rt fe O a</td><td>EGR1</td><td>rt fe O a</td><td>rt fe Ü a</td><td>rt fe O a</td><td>EGRl</td><td>EGRl</td><td>EGRl</td><td>EGRl</td><td>rt fe O a</td><td>rt fe O a</td><td>rt fe O a</td><td>rt fe O a</td><td>EGRl</td><td>EGRl</td><td>rt fe O a</td><td>rt O a</td><td>rt fe O a</td><td>rt fe O . a</td><td>rt fe O a</td><td>rt fe O a</td><td>rt fe O a</td>

<td>Peso de la sonda</td><td>o Cí</td><td>oo rt</td><td>!· rt</td><td>to rt</td><td>to rt</td><td>OI rt</td><td>rt rt</td><td>O rt</td><td>&lt;n</td><td>&lt;n</td><td> «0</td><td>o</td><td>o*</td><td>r·</td><td>o-</td><td>«P</td><td>P</td><td> **</td><td>OI</td><td>Cí</td><td>rt</td><td>rt</td>

<td>Gen Co- expresado</td><td>rt to fe δ</td><td>to to fe fe 03</td><td>CSRNPl</td><td>NR4A3</td><td>EGR3</td><td>to fe a</td><td>RHOB</td><td>DUSPl</td><td>ATF3</td><td></td><td>fe ! fe H</td><td>NFKBIZ</td><td>N R4A2</td><td></td><td>IER2</td><td>MCLl</td><td>faith to</td><td>OI faith OR to</td><td>NEDD9</td><td>SRF</td><td>GADD45B</td><td>TRIBl</td>

<td>Stack Id</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td></td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td><td>to</td>

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Example 4: Prospective Validation Study of RS27

Study Design and Statistical Methods

The RS27 algorithm in Table 4 was tested in a prospective clinical validation study that included 395 evaluable patients who had surgery for their prostate cancer between 1997 and 2010 at the University of California, San Francisco (UCSF). Patients were at Low or Intermediate (CAPRA) risk for clinically localized prostate cancer who may have been reasonable candidates for active surveillance but underwent RP at UCSF within 6 months of biopsy diagnosis of prostate cancer. No randomization was performed for patient selection. For each patient, prostate biopsy samples from a fixed paraffin embedded tissue block (FPET) containing one or more tumor-containing needle nuclei were evaluated.

To investigate whether there is a significant relationship between RS27 or any component of RS27 and adverse pathology in RP, multivariable and univariable multinomial logistic regression models were used and the p values ​​of the odds ratio (LR) tests of the annular hypothesis were reported. that the odds ratio (OR) is one. The multinomial logistic model was also used to cal culate estimates with 95% confidence intervals of the probability of high-grade disease or

145 not confined to organs. To assess the relationship between RS27, baseline co-variables, and combinations of these factors with high-grade or non-organ confined disease, multivariable and non-variable binary logistic regression models were used, and the p-values ​​of The odds ratio tests the null hypothesis that the odds ratio (OR) is one.

The primary end point was formulated as follows:

Table 12: Clinical End Point - Grade and RP Stage

<td>Register of Gleason RP</td><td>Stage T2 Pathological</td><td>Pathological Stage T3</td>

<td> £3+3</td><td> 1</td><td> 2</td>

<td> 3+4</td><td> 3</td><td> 4</td>

<td>Major pattern 4 or minor pattern 5th pattern tertiary 5</td><td> 5</td><td> 6</td>

where the record of Gleason ^ 3 + 3 and pT2 (indicated 1) is the reference category and all other categories (2-6) will be compared to the category a reference.

The cell combinations from Table 12 evaluated in the binary logistic regression models include the following:

Cells 2, 4, 6vs. 1, 3, 5: disease not confined to organs

146

Cells 5, 6 vs. 1, 2, 3, 4: high-grade disease Cells 2, 4, 5, 6 vs. Iy3: high-grade or non-organ confined disease.

RS27 algorithm

RS27 on a scale of 0 to 100 was derived from the reference normalized gene expression measurements as follows.

The unscaled RS27 (RS27u) was defined as in the Table:

RS27u group = 0.735 * ECM (Response to Stromal) - migration group 0.368 * (Cell Organization) - group 0.352 * PSA (Androgen) Proliferation + 0.095 * (TPX2)

Where:

ECM Group Record (Stromal Response) =

0.527 * BGN + 0.457 * COL1A1 + 0.156 * SFRP4

Registration of the migration group (Cellular Organization) =

0.163 * FLN C + 0.504 * GSN + 0.421 * TPM2 + 0.394 * GSTM2

PSA group record (Androgen) = 0.634 * FAM13C +

1,079 * KLK2 + 0.642 * AZGPl + 0.997 * SRD5A2 Thresh

Proliferation register (TPX2) = TPX2 threshold where the threshold gene registers for SRD5A2 and TPX2 are calculated as follows:

Threshold SRD5A2 = '5.5

SRD5A2

If SRD5A2 &lt;5.5 otherwise

147

Í5.0 if TPX2 &lt;5.0

TPX2 threshold = &lt;

(TPX2 otherwise

RS27u is then scaled again to be between 0 and 100 as follows:

RS27 (scaled) if 13.4 x (RS27u + l 0.5) &lt;0 13.4 x (RS27u + 10.5) if 0 &lt;13.4 x (RS27u + 10.5) &lt;100

100 yes 13.4 x (RS27U + 10.5)&gt; 100

Patients were classified into low RS27, high intermediate groups using the prespecified cutoff points defined in Table 13 below. These cut-off points defined the limits between the low RS27 groups and inter media and between RS27 groups. The cut-off points were derived from the discovery study with the intention of identifying substantial proportions of patients who, on average, had a relatively significant low or high risk of adverse pathology. RS27 was rounded to the nearest whole number before the cutoff points defining RS27 groups are applied.

Table 13

<td>RS27 group</td><td>Registry</td>

<td>Low</td><td>Less than 16</td>

<td>Intermediate</td><td>Greater than or equal to 16 and less that 3 0</td>

<td>High</td><td>Greater than or equal to 30</td>

148 *&gt;5

Test methods

Paraffin from samples was removed with Xylene Shandon substitute (Thermo Scientific, Kalamazoo, MI). Nucleic acids were isolated using the Agencourt ^ FormaPure * ® XP Kit (Beckman Coulter, Beverly, MA).

The amount of RNA was determined using the Quant-iT ^ RiboG RNA Assay Kit reen^MR (Invitrogen ^, Carlsbad, CA). The quantified RNA was converted to complementary DNA using the Omniscript kit^MR (Qiagen, Valencia, CA) and combined with the reverse primers for the 12 RS27 genes and 5 normalization genes (ARF1, ATP5E, CLTC, GPS1, PGK1) as shown in Table A. The reaction was incubated at 37 ° C for 60 minutes and then inactivated at 93 ° C for 5 minutes.

CDNA was pre-amplified using a TaqMan master mix^MR Tailor made PreAmp for Genomic Health, Inc. by Life Technologies (Carlsbad, CA) and forward and reverse primers for all targets as shown in Table A. The reaction was placed in a thermocycler (DNA Engine^MR PTC 200G, Bio-Rad, Hercules, CA) and incubated under the following conditions: A) 95 ° C for 15 sec; B) 60 ° C for 4 min; C) 95 ° C for 15 sec; and D) stages B and C were repeated They went 8 times. The amplified product was then mixed with the forward and reverse primers and probes for each of the

149 Target as shown in Table A and the QuantiTect Primer Assay Master Mix^MR (Qiagen, Valencia, CA) and amplified for 45 cycles on LightCycler^MR 480 (Roche Applied Science, Indianapolis, IN). The expression level was calculated using the crossing point method. (Cp).

Results

RS27 significantly predicted adverse pathology, from non-organ confined disease, high-grade disease, and high-grade or non-organ confined disease, and adds value beyond the Gleason record as shown in Tables 14, 15, 16 , and 17, respectively.

Table 14 Prediction of Adverse Pathology

<td>Variable</td><td>Chi squared Li</td><td>DF</td><td>P-value</td>

<td>RS27 registration</td><td> 19.31</td><td> 5</td><td> 0.002</td>

<td>Gleason Biopsy Record Central 3 + 4 vs 3 + 3</td><td> 32.86</td><td> 5</td><td> &lt;0.001</td>

The results obtained from the multivariable multinomial logistic model for cells 2, 3, 4, 5, and 6 vs 1 in Table 12.

DF = degrees of freedom

150

Table 15 Prediction of Non-Organ Confined Disease

<td>Model</td><td>Variables</td><td>Relation of Possibilities</td><td>95% Interval Confidence</td><td>DF</td><td>Chi al Square LR</td><td>P-value</td>

<td colspan="2">Univariate Model</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>RS27</td><td> 2.20</td><td> (1.46,3.31)</td><td> 1</td><td> 14.44</td><td> &lt;0.001</td>

<td colspan="2">Multivariable Model</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>RS27</td><td> 1.93</td><td> (1.25,2.96)</td><td> 1</td><td> 8.97</td><td> 0.003</td>

<td></td><td>Gleason Biopsy Record Central 3 + 4 vs 3 + 3</td><td> 1.79</td><td> (1.04,3.10)</td><td> 1</td><td> 4.23</td><td> 0.040</td>

Results obtained from univariate and multivariable binary logistic regression models for cells

2, 4, 6 vs. 1, 3, 5 in Table 12

Odds ratio for RS27 was per 20 unit increase

Table 16 prediction d high-grade disease

<td>Model</td><td>Variables</td><td>Relation of Possibilities</td><td>95% Interval Confidence</td><td>DF</td><td>Chi al Square LR</td><td>P-value</td>

<td colspan="2">Univariate Model</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>RS27</td><td> 2.48</td><td> (1.60,3.85)</td><td> 1</td><td> 16.78</td><td> &lt;0.001</td>

<td colspan="2">Multivariable Model</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>RS27</td><td> 2.32</td><td> (1.46,3.67)</td><td> 1</td><td> 12.92</td><td> &lt;0.001</td>

<td></td><td>Gleason record 3 + 4 Central Biopsy vs3 + 3</td><td> 1.36</td><td> (0.75,2.47)</td><td> 1</td><td> 0.98</td><td> 0.322</td>

Univariate and multivariable binary logistic regression models for cells 5, 6 vs. 1-4 in Table 12

151 ^; '55

Odds ratio for RS27 was per 20 unit increase

Table 17 Prediction of high-grade or non-organ confined disease

<td>Model</td><td>Variables</td><td>Relation of Possibilities</td><td>95% Interval Confidence</td><td>DF</td><td>Chi al Square LR</td><td>P-value</td>

<td colspan="2">Univariate Model</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>RS27</td><td> 2.23</td><td> (1.52,3.27)</td><td> 1</td><td> 17.77</td><td> &lt;0.001</td>

<td colspan="2">M Multivariable model</td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>RS27</td><td> 1.93</td><td> (1.30,2.88)</td><td> 1</td><td> 10.70</td><td> 0.001</td>

<td></td><td>Gleason record of Central Biopsy 344 vs343</td><td> 1.94</td><td> (1.17,3.21)</td><td> 1</td><td> 6.45</td><td> 0.011</td>

* Results obtained from non-variable and multivariable binary logistic regression models for cells 2, 4, 5, vs. 1, 3 in Table 12

Odds ratio for RS17 was per 20 unit increase

Furthermore, RS27 predicted adverse pathology beyond conventional clinical / pathological treatment factors as shown in Table 18.

152

Table 18 Prediction of Adverse Pathology Beyond Conventional Clinical / Pathological Treatment Factors

<td>Variable</td><td>Chi squared LR</td><td>DF</td><td>P-value</td>

<td>RS27</td><td> 21.46</td><td> 5</td><td> &lt;0.001</td>

<td>Gleason Biopsy Record Original</td><td> 22.77</td><td> 5</td><td> &lt;0.001</td>

<td></td><td></td><td></td><td></td>

<td>RS27</td><td> 19.31</td><td> 5</td><td> 0.002</td>

<td>Gleason Biopsy Record Central</td><td> 32.86</td><td> 5</td><td> &lt;0.001</td>

<td></td><td></td><td></td><td></td>

<td>RS27</td><td> 30.09</td><td> 5</td><td> &lt;0.001</td>

<td>Clin T2 v. YOU</td><td> 11.94</td><td> 5</td><td> 0.036</td>

<td></td><td></td><td></td><td></td>

<td>RS27</td><td> 30.17</td><td> 5</td><td> &lt;0.001</td>

<td>Baseline PSA (ng / ml) &lt;10 v. &gt; = 10</td><td> 10.44</td><td> 5</td><td> 0.064</td>

<td></td><td></td><td></td><td></td>

<td>RS27</td><td> 30.75</td><td> 5</td><td> &lt;0.001</td>

<td>Continuous PSA</td><td> 15.17</td><td> 5</td><td> 0.010</td>

<td></td><td></td><td></td><td></td>

<td>RS27</td><td> 26.36</td><td> 5</td><td> &lt;0.001</td>

<td>Age</td><td> 19.05</td><td> 5</td><td> 0.002</td>

<td></td><td></td><td></td><td></td>

<td>RS27</td><td> 29.20</td><td> 5</td><td> &lt;0.001</td>

<td>Pct Positive Core</td><td> 4.75</td><td> 5</td><td> 0.447</td>

When added to conventional clinical / pathological tools such as CAPRA, RS27 further refined the risk of high-grade or non-organ confined disease. Using CAPRA alone, 5% of patients

153 identified as having a greater than 85% probability of being free of high-grade or non-organ-confined disease compared to 22% of patients identified as being free of high-grade or non-organ-confined disease using RS27 in addition to CAPRA (Figure 8 ).

When added to conventional clinical / pathological tools such as AUA (D'Amico et al., JAMA 280: 969-974, 1998), RS27 further refines the risk of high-grade or non-organ-confined disease. As shown in Figure 9, using the AUA alone, 0% of patients are identified as having a greater than 80% chance of being free of high-grade or non-organ confined disease compared to 27% of patients identified to be free of high-grade or non-organ-confined disease. using GPS in addition to AUA.

Individual genes and RS27 gene clusters were also associated with adverse pathology, high-grade disease, non-organ confined disease, and high-grade or non-organ confined disease, in Univariate Analysis as shown in Tables 19 , 20, 21, and 22, respectively.

154

<img file="MX366164B_D0034.tif" />

Table 19 Association of Genes and Gene Groups with Pathology

Adverse, Univariate Analysis

<td>Genes and Gene Group</td><td>Chi squared LR</td><td>DF</td><td>P-value</td>

<td>BGN</td><td> 7.11</td><td> 5</td><td> 0.213</td>

<td>COL1A1</td><td> 7.88</td><td> 5</td><td> 0.163</td>

<td>SFRP4</td><td> 8.87</td><td> 5</td><td> 0.114</td>

<td>FLNC</td><td> 12.26</td><td> 5</td><td> 0.031</td>

<td>GSN</td><td> 5.73</td><td> 5</td><td> 0.333</td>

<td>GSTM2</td><td> 1.84</td><td> 5</td><td> 0.870</td>

<td>TPM2</td><td> 18.33</td><td> 5</td><td> 0.003</td>

<td>AZGP1</td><td> 22.87</td><td> 5</td><td> &lt;0.001</td>

<td>KLK2</td><td> 5.97</td><td> 5</td><td> 0.309</td>

<td>PAM13C1</td><td> 21.55</td><td> 5</td><td> &lt;0.001</td>

<td>SRD5A2</td><td> 9.10</td><td> 5</td><td> 0.105</td>

<td>SRD5A2 Formado en umbral</td><td> 9.25</td><td> 5</td><td> 0.099</td>

<td>TPX2</td><td> 14.26</td><td> 5</td><td> 0.014</td>

<td>TPX2 Formado en umbral</td><td> 23.34</td><td> 5</td><td> &lt;0.001</td>

<td>Promedio del Gen Ref</td><td> 3.27</td><td> 5</td><td> 0.659</td>

<td>Registro del Grupo Estromal</td><td> 9.84</td><td> 5</td><td> 0.080</td>

<td>Registro del Grupo de Organización Celular</td><td> 8.04</td><td> 5</td><td> 0.154</td>

<td>Registro del Grupo de Andrógeno</td><td> 29.46</td><td> 5</td><td> &lt;0.001</td>

<td>Registro del Grupo de Proliferación</td><td> 23.34</td><td> 5</td><td> &lt;0.001</td>

<td>GPS</td><td> 29.98</td><td> 5</td><td> &lt;0.001</td>

155

Tabla 20 Asociación de Genes y Grupos de Genes con Enfermedad de Alto Grado, Análisis Univariables

<td>Gen</td><td>Chi al Cuadrado</td><td>DF</td><td>Valor p</td><td>OR</td><td> (95%</td><td>de CI)</td>

<td>BGN</td><td> 3.67</td><td> 1</td><td> 0.055</td><td> 1.46</td><td> (0.99,</td><td> 2.15)</td>

<td>COL1A1</td><td> 2.33</td><td> 1</td><td> 0.127</td><td> 1.32</td><td> (0.93,</td><td> 1.87)</td>

<td>SFRP4</td><td> 6.08</td><td> 1</td><td> 0.014</td><td> 1.33</td><td> (1.06,</td><td> 1.67)</td>

<td>FLNC</td><td> 3.04</td><td> 1</td><td> 0.081</td><td> 0.77</td><td> (0.57,</td><td> 1.03)</td>

<td>GSN</td><td> 0.14</td><td> 1</td><td> 0.710</td><td> 0.94</td><td> (0.67,</td><td> 1.32)</td>

<td>GSTM2</td><td> 0.03</td><td> 1</td><td> 0.870</td><td> 0.97</td><td> (0.69,</td><td> 1.37)</td>

<td>TPM2</td><td> 2.85</td><td> 1</td><td> 0.091</td><td> 0.76</td><td> (0.56,</td><td> 1.04)</td>

<td>AZGP1</td><td> 12.69</td><td> 1</td><td> &lt;0.001</td><td>0.5B</td><td> (0.42,</td><td> 0.79)</td>

<td>KLK2</td><td> 3.50</td><td> 1</td><td> 0.061</td><td> 0.62</td><td> (0.38,</td><td> 1.02)</td>

<td>FAM13C1</td><td> 9.29</td><td> 1</td><td> 0.002</td><td> 0.51</td><td> (0.33,</td><td> 0.79)</td>

<td>SRD5A2</td><td> 3.26</td><td> 1</td><td> 0.071</td><td> 0.76</td><td> (0.56,</td><td> 1.02)</td>

<td>SRD5A2 Formado en umbral</td><td> 2.70</td><td> 1</td><td> 0.100</td><td> 0.75</td><td> (0.53,</td><td> 1.06)</td>

<td>TPX2</td><td> 1.72</td><td> 1</td><td> 0.190</td><td> 1.21</td><td> (0.91,</td><td> 1.59)</td>

<td>TPX2 Formado en umbral</td><td> 7.38</td><td> 1</td><td> 0.007</td><td> 1.93</td><td> (1.20,</td><td> 3.11)</td>

<td>Promedio del Gen Ref</td><td> 1.18</td><td> 1</td><td> 0.277</td><td> 0.86</td><td> (0.65,</td><td> 1.14)</td>

<td>Registro del Grupo de Respuesta Estromal</td><td> 4.92</td><td> 1</td><td> 0.027</td><td> 1.49</td><td> (1.05,</td><td> 2.12)</td>

<td>Registro del Grupo de Organización Celular</td><td> 1.12</td><td> 1</td><td> 0.290</td><td> 0.87</td><td> (0.66,</td><td> 1.13)</td>

<td>Registro del Grupo de Andrógeno</td><td> 15.07</td><td> 1</td><td> &lt;0.001</td><td> 0.69</td><td> (0.58,</td><td> 0.83)</td>

<td>Registro del Grupo de Proliferación</td><td> 7.38</td><td> 1</td><td> 0.007</td><td> 1.93</td><td> (1.20,</td><td> 3.11)</td>

156

Tabla 21 Asociación de Genes y Grupos de Genes con Enfermedad

Confinada no a Órganos, Análisis Univariable

<td>Gen</td><td>Chi al Cuadrado</td><td>DF</td><td>Valor p</td><td>OR</td><td>(95% de Cl)</td>

<td>BGN</td><td> 2.58</td><td> 1</td><td> 0.109</td><td> 1.34</td><td> (0.94, 1.91)</td>

<td>COL1A1</td><td> 2.90</td><td> 1</td><td> 0.089</td><td> 1.33</td><td> (0.96, 1.83)</td>

<td>SFRP4</td><td> 4.39</td><td> 1</td><td> 0.036</td><td> 1.25</td><td> (1.01, 1.54)</td>

<td>PLNC</td><td> 0.34</td><td> 1</td><td> 0.560</td><td> 0.92</td><td> (0.70, 1.21)</td>

<td>GSN</td><td> 0.27</td><td> 1</td><td> 0.603</td><td> 0.92</td><td> (0.67, 1.26)</td>

<td>GSTM2</td><td> 0.16</td><td> 1</td><td> 0.693</td><td> 0.94</td><td> (0.68, 1.29)</td>

<td>ΓΡΜ2</td><td> 0.51</td><td> 1</td><td> 0.473</td><td> 0.9</td><td> (0.67, 1.20)</td>

<td>AZGP1</td><td> 12.48</td><td> 1</td><td> &lt;0.001</td><td> 0.59</td><td> (0.44, 0.80)</td>

<td>KLK2</td><td> 2.10</td><td> 1</td><td> 0.148</td><td> 0.71</td><td> (0.45, 1.12)</td>

<td>FAM13C1</td><td> 12.42</td><td> 1</td><td> 0.000</td><td> 0.48</td><td> (0.32, 0.73)</td>

<td>SRD5A2</td><td> 2.42</td><td> 1</td><td> 0.120</td><td> 0.8</td><td> (0.60, 1.06)</td>

<td>SRD5A2 Formado en umbral</td><td> 2.65</td><td> 1</td><td> 0.103</td><td> 0.77</td><td> (0.56, 1.06)</td>

<td>ΓΡΧ2</td><td> 6.38</td><td> 1</td><td> 0.012</td><td> 1.39</td><td> (1.08, 1.81)</td>

<td>ΓΡΧ2 Formado en umbral</td><td> 6.51</td><td> 1</td><td> 0.011</td><td> 1.82</td><td> (1.14, 2.89)</td>

<td>Promedio del Gen Ref</td><td> 0.33</td><td> 1</td><td> 0.563</td><td> 0.93</td><td> (0.73, 1.19)</td>

<td>Registro del Grupo de Respuesta Estromal</td><td> 4.24</td><td> 1</td><td> 0.040</td><td> 1.41</td><td> (1.02, 1.95)</td>

<td>Registro del Grupo de Organización Celular</td><td> 0.45</td><td> 1</td><td> 0.504</td><td> 0.92</td><td> (0.72, 1.18)</td>

<td>Registro del Grupo de Andrógeno</td><td> 14.64</td><td> 1</td><td> &lt;0.001</td><td> 0.71</td><td> &lt;0.60, 0.85)</td>

<td>Registro del Grupo de Proliferación</td><td> 6.51</td><td> 1</td><td> 0.011</td><td> 1.82</td><td> (1.14, 2.89)</td>

157

Tabla 22 Asociación de Genes y Grupos de Genes con Enfermedad de alto grado o Confinada no a Órganos, Análisis Univariable

<td>Gen</td><td>Chi al Cuadrado</td><td>DF</td><td>Valor p</td><td>Relación de Posibilidades</td><td> (95%</td><td>de CI)</td>

<td>BGN</td><td> 3.15</td><td> 1</td><td> 0.076</td><td> 1.33</td><td> (0.97,</td><td> 1.84)</td>

<td>COL1A1</td><td> 1.96</td><td> 1</td><td> 0.162</td><td> 1.23</td><td> (0.92,</td><td> 1.65)</td>

<td>SFRP4</td><td> 7.08</td><td> 1</td><td> 0.008</td><td> 1.29</td><td> (1.07,</td><td> 1.55)</td>

<td>FLNC</td><td> 2.36</td><td> 1</td><td> 0.125</td><td> 0.83</td><td> (0.65,</td><td> 1.06)</td>

<td>GSN</td><td> 0.45</td><td> 1</td><td> 0.503</td><td> 0.91</td><td> (0.68,</td><td> 1.20)</td>

<td>GSTM2</td><td> 0.49</td><td> 1</td><td> 0.484</td><td> 0.9</td><td> (0.68,</td><td> 1.20)</td>

<td>TPM2</td><td> 2.24</td><td> 1</td><td> 0.135</td><td> 0.82</td><td> (0.63,</td><td> 1.06)</td>

<td>AZGP1</td><td> 12.20</td><td> 1</td><td> 0.001</td><td> 0.61</td><td> (0.46,</td><td> 0.82)</td>

<td>KLK2</td><td> 2.18</td><td> 1</td><td> 0.140</td><td> 0.73</td><td> (0.48,</td><td> 1.11)</td>

<td>FAM13C1</td><td> 11.13</td><td> 1</td><td> 0.001</td><td> 0.53</td><td> (0.37,</td><td> 0.78)</td>

<td>SRD5A2</td><td> 4.36</td><td> 1</td><td> 0.037</td><td> 0.76</td><td> (0.59,</td><td> 0.98)</td>

<td>SRD5A2 Formado en umbral</td><td> 4.63</td><td> 1</td><td> 0.032</td><td> 0.73</td><td> (0.55,</td><td> 0.98)</td>

<td>ΓΡΧ2</td><td> 3.50</td><td> 1</td><td> 0.062</td><td> 1.25</td><td> (0.99,</td><td> 1.58)</td>

<td>TPX2 Formado en umbral</td><td> 5.86</td><td> 1</td><td> 0.016</td><td> 1.73</td><td> (1.09,</td><td> 2.74)</td>

<td>Promedio del Gen Ref</td><td> 0.68</td><td> 1</td><td> 0.041</td><td> 0.91</td><td> (0.73,</td><td> 1.14)</td>

<td>Registro del Grupo de Respuesta Estromal</td><td> 4.59</td><td> 1</td><td> 0.032</td><td> 1.37</td><td> (1.03,</td><td> 1.84)</td>

<td>Registro del Grupo de Organización Celular</td><td> 1.54</td><td> 1</td><td> 0.215</td><td> 0.87</td><td> (0.70,</td><td> 1.08)</td>

<td>Registro del Grupo de Andrógeno</td><td> 16.56</td><td> 1</td><td> &lt;0.001</td><td> 0.72</td><td> (0.61,</td><td> 0.84)</td>

<td>Registro del Grupo de Proliferación</td><td> 5.86</td><td> 1</td><td> 0.016</td><td> 1.73</td><td> (1.09,</td><td> 2.74)</td>

Example 5: RS27 Adds Value Beyond the State

PTEN / TMPRSS2-ERG in Predicting Clinical Recurrence

The PTEN mutation and the TMPRSS2-ERG fusion genes are

158 commonly associated with poor prognosis for prostate cancer. At this point, RS27 was analyzed to determine if it can provide value beyond PTEN / TMPRSS2-ERG status in predicting clinical recurrence.

PTEN and TMPRSS2-ERG fusion expression levels obtained in the gene identification study described in Example 1 above and in US publication No. 20120028264 were used to stratify patients into low PTEN and normal PTEN groups. The PTEN and TMPRSS2-ERG (T2-ERG) status of the patients were found as: Table 23. Distribution of the expression of PTEN by the State

T2-ERG

<td></td><td>T2-ERG Negative (53%)</td><td>T2-ERG (47%)</td><td>Positive</td>

<td>PTEN Medium</td><td> 8.9</td><td colspan="2"> 8.7</td>

<td>25% PTEN</td><td> 8.7</td><td colspan="2"> 8.4</td>

A cutoff point for low PTEN was made at &lt;= 8.5, which included approximately 13% of T2-ERG negative patients and 28% of T2-ERG positive patients. Normal PTEN was defined as&gt; 8.5.

The Cox Univariables provided hazards were applied to assess the association between PTEN status and time to clinical recurrence (cR). Figure 10 and Table 24 show that patients with low PTEN have a

159 higher risk of recurrence compared to patients with normal PTEN.

Table 24.

Chi squared P value RH 95% Cl

12.44 &lt;0.001 0.38 (0.22,0.65)

When patients were additionally certified in

Low PTEN / negative T2-ERG (category 0), low PTEN / positive T2-ERG (category 1), normal PTEN / negative T2-ERG (category 2), and normal PTEN / positive T2-ERG (category

<td>3), both categories</td><td>from PTEN ba jo</td><td>had the</td><td>rates of</td>

<td>lower recurrence</td><td>Compared to</td><td>the patients</td><td>with PTEN</td>

<td>normal as shown</td><td>in Figure 11</td><td>and Table 25</td><td> •</td>

<td></td><td>Table 25.</td><td></td><td></td>

<td>PTEN / T2-ERG Categories</td><td>Spark</td><td>VALUE P</td><td>95% Cl</td>

<td>Cat 1 v 0</td><td> 0.93</td><td> 0.34</td><td> (0.28,1.55)</td>

<td>Cat 2 v 0</td><td> 11.80</td><td> &lt;0.01</td><td> (0.12,0.56)</td>

<td>Cat 3 v 0</td><td> 7.05</td><td> 0.01</td><td> (0.16,0.76)</td>

The tables below summarize the results of a multivariable model with PTEN / T2-ERG status (Table 26) or PTEN status (Table 27), RS27, and Gleason record of

Biopsy (Bx GS), showing that RS27 adds value beyond Biopsy's PTEN and T2-ERG and GS markers in predicting clinical recurrence.

160

Table 26.

<td>VARIABLE</td><td>DF</td><td>Spark</td><td>VALUE P</td><td>HR</td><td>95% DE Cl</td>

<td>RS27</td><td> 1</td><td> 64.13</td><td> &lt;0.01</td><td> 1.07</td><td> (1.05,1.09)</td>

<td>PTEN / T2-ERG status</td><td> 3</td><td> 1.59</td><td> 0.66</td><td></td><td></td>

<td>PTEN / T2-ERG (Cat 1</td><td> 1</td><td> 0.06</td><td> 0.80</td><td> 0.91</td><td> (0.41,1.98)</td>

<td>v. 0)</td><td></td><td></td><td></td><td></td><td></td>

<td>PTEN/T2-ERG (Cat 2</td><td> 1</td><td> 1.17</td><td> 0.28</td><td> 0.65</td><td> (0.29,1.42)</td>

<td>V. 0)</td><td></td><td></td><td></td><td></td><td></td>

<td>PTEN/T2-ERG (Cat 3</td><td> 1</td><td> 0.14</td><td> 0.71</td><td> 0.86</td><td> (0.39,1.89)</td>

<td>v. 0)</td><td></td><td></td><td></td><td></td><td></td>

<td>BXGS</td><td> 2</td><td> 7.19</td><td> 0.03</td><td></td><td></td>

<td>BxGS (7 v. 6)</td><td> 1</td><td> 6.86</td><td> 0.01</td><td> 0.40</td><td> (0.20,0.79)</td>

<td>BxGS (8+ v. 6)</td><td> 1</td><td> 1.35</td><td> 0.24</td><td> 0.69</td><td> (0.36,1.29)</td>

Tabla 27.

<td>VARIABLE</td><td>DF</td><td>CHISQ</td><td>VALOR P</td><td>HR</td><td>95% DE Cl</td>

<td>GPS</td><td> 1</td><td> 66.67</td><td> &lt;0.01</td><td> 1.07</td><td> (1.05,1.09)</td>

<td>PTEN Status</td><td> 1</td><td> 0.86</td><td> 0.35</td><td> 0.78</td><td> (0.46,1.32)</td>

<td>BXGS</td><td> 2</td><td> 6.43</td><td> 0.04</td><td></td><td></td>

<td>BxGS (7 v.</td><td> 1</td><td> 6.12</td><td> 0.01</td><td> 0.42</td><td> (0.21,0.84)</td>

<td> 6)</td><td></td><td></td><td></td><td></td><td></td>

<td>BxGS (8+ v.</td><td> 1</td><td> 1.15</td><td> 0.28</td><td> 0.71</td><td> (0.37,1.33)</td>

<td>δ)</td><td></td><td></td><td></td><td></td><td></td>

161

Tabla

<td>8 3 w</td><td></td><td></td><td> 8 1</td><td></td><td>i</td><td></td><td></td><td></td><td></td><td>j</td><td> &lt;</td><td></td><td> 1</td><td></td><td></td><td></td><td>s</td><td></td><td></td><td> §</td><td></td><td></td><td></td><td></td><td> \</td><td> 1</td><td>g</td><td></td><td>j</td><td></td><td></td><td></td><td>s</td>

<td> 0..</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 0</td><td></td><td>f-</td><td></td><td> 0</td><td> 0</td><td> 0</td><td>r-</td><td>r-l</td><td> 0</td><td> 0</td><td> 0</td><td>Γ*</td><td>«d</td><td> 0</td><td> 0</td><td> 0</td><td>r-</td><td>id</td><td> 0</td><td> 0</td><td> 0</td><td>P-</td><td>id</td>

<td>gS w</td><td></td><td></td><td>id</td><td>id</td><td>d</td><td>Oí</td><td>OJ</td><td>n</td><td> 0</td><td> 0</td><td>tí</td><td>tí</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td>t-</td><td></td><td>r-</td><td></td><td></td><td></td><td></td><td></td><td>r-l</td><td>id</td><td>id</td><td>id</td><td>rd</td><td>id</td><td>íd</td><td>id</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>m</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>A</td><td></td><td></td>

<td></td><td></td><td></td><td>g</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>_n</td><td></td><td></td><td> $</td><td>_n</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 2</td><td></td><td></td><td></td><td></td><td></td><td> $</td><td></td><td></td>

<td> $</td><td>g</td><td> $</td><td></td><td> $</td><td>G</td><td> |</td><td>U</td><td>s</td><td> 8</td><td>Lj</td><td>a</td><td></td><td>b</td><td> §</td><td>P</td><td> 8</td><td>fe</td><td>R</td><td>o</td><td></td><td>P</td><td>a</td><td></td><td> 8</td><td>δ</td><td></td><td>Éj</td><td>A</td><td>g</td><td>R</td><td> £</td><td> £&gt;</td><td></td>

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<td>u</td><td>y</td><td>H</td><td> 4,</td><td>H</td><td> 4.</td><td>H</td><td>Π</td><td></td><td>n</td><td>y</td><td>n</td><td>ü</td><td>i</td><td></td><td>P</td><td>n</td><td>Π</td><td></td><td> 3</td><td>y</td><td>fj,</td><td>jj</td><td>X</td><td>A</td><td></td><td>P</td><td>L¡</td><td>p</td><td> 0</td><td>A</td><td>rí</td><td>H</td><td>Γπ</td>

<td> 8</td><td>s</td><td>s</td><td> 8</td><td> 8</td><td>R</td><td> 8</td><td></td><td></td><td>fe</td><td> 8</td><td>ς</td><td> $</td><td> 8</td><td>b</td><td> 8</td><td>s</td><td>fe-</td><td></td><td> 8</td><td> 8</td><td>á</td><td> 8</td><td>g</td><td> 8</td><td>R</td><td>a</td><td> 8</td><td>B</td><td> 8</td><td>R</td><td> $</td><td></td><td></td>

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<td>w</td><td>g</td><td>fe</td><td> §</td><td> §</td><td>B</td><td>y</td><td> 8</td><td>c</td><td> 8</td><td>b</td><td></td><td>g</td><td>g</td><td> 3</td><td> 8</td><td> 8</td><td> 8</td><td> 8</td><td>á</td><td> 8</td><td>i</td><td> 8</td><td>p</td><td> 8</td><td> 0</td><td> 8</td><td> 3</td><td> 8</td><td>B</td><td> 3</td><td></td><td>fe</td><td>b</td>

<td> 0 ..</td><td></td><td></td><td></td><td></td><td></td><td></td><td> 0</td><td>o</td><td></td><td>co</td><td></td><td> 0</td><td>o</td><td>tí</td><td>oo</td><td>Oí</td><td> 0</td><td>o</td><td>tí</td><td> 0</td><td></td><td> 0</td><td>o</td><td>tí</td><td> 0</td><td>Oí</td><td> 0</td><td>O</td><td>tí</td><td> 0</td><td>(tí</td><td> 0</td><td>O</td>

<td>@S TO</td><td></td><td></td><td>i-1</td><td>td</td><td>d</td><td> 0</td><td>OJ</td><td> 0</td><td> 0</td><td> 0</td><td>tí</td><td>tí</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>rd</td><td>id</td><td>id</td><td>id</td><td>r-l</td><td>id</td><td>id</td><td>id</td>

<td>M</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>S</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 8</td><td>i</td><td>Ϊ</td><td>H</td><td>G</td><td></td><td>g</td><td></td><td>g</td><td></td><td>i</td><td> 1</td><td></td><td> 1</td><td> 1</td><td>B</td><td> 1</td><td>i</td><td>a</td><td>g</td><td>i</td><td>g</td><td> 13</td><td></td><td>I</td><td>s</td><td></td><td> 8</td><td> 3</td><td>i</td><td>I</td><td>i</td><td></td><td></td>

<td></td><td>P</td><td></td><td>S</td><td>R</td><td></td><td> §</td><td> $</td><td></td><td></td><td> 1</td><td>i</td><td>b</td><td></td><td></td><td> §</td><td>R</td><td> 0</td><td> 8</td><td>e</td><td>a</td><td> 8</td><td> 8</td><td> 1</td><td>É</td><td>P</td><td></td><td>g</td><td>P</td><td></td><td> 8</td><td></td><td></td><td>y</td>

<td>« p</td><td></td><td> $</td><td>Q</td><td>fe</td><td>R</td><td>R</td><td>B</td><td> 3</td><td>Jgj</td><td>R</td><td></td><td>a</td><td></td><td>ü</td><td> 8</td><td></td><td> 3</td><td> 8</td><td> 3</td><td>y</td><td>ϋ</td><td> 3</td><td>y</td><td> 3</td><td>D</td><td> 8</td><td> 3</td><td>D</td><td>s</td><td>Q</td><td></td><td></td><td>a</td>

<td>rl M</td><td>r</td><td>ü</td><td></td><td>u</td><td> $</td><td>y</td><td></td><td>tí</td><td></td><td> 2</td><td>g</td><td> 8</td><td></td><td> 2</td><td></td><td></td><td>t}</td><td>f£</td><td> 8</td><td>p</td><td></td><td> 9</td><td>p</td><td>R</td><td> 3</td><td> 3</td><td> □</td><td>Γ</td><td> 3</td><td>n</td><td>p</td><td>n</td><td>b</td>

<td>y §</td><td>g</td><td>g</td><td>q</td><td>R</td><td> 8</td><td></td><td></td><td>g</td><td>g</td><td> 0</td><td>fe</td><td> §</td><td>i</td><td> 9</td><td>p</td><td>a</td><td></td><td> 8</td><td> 8</td><td> 8</td><td></td><td> 8</td><td> 9</td><td>R</td><td>δ</td><td>a</td><td></td><td>fe</td><td> 8</td><td> 0</td><td>P</td><td></td><td> 9</td>

<td>3g</td><td>e</td><td>g</td><td> 8</td><td> 0</td><td>g</td><td>b</td><td>i</td><td>i</td><td> 8</td><td> 1</td><td> §</td><td>g</td><td> 8</td><td> 8</td><td>a</td><td> 8</td><td> 8</td><td> !</td><td>S</td><td> 8</td><td>Sí</td><td> 8</td><td> 8</td><td>á</td><td>fe</td><td></td><td>g</td><td> *</td><td>b</td><td>a</td><td>b</td><td> 8</td><td> 8</td>

<td> 0 ..</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>σι</td><td></td><td>r-</td><td></td><td> 0</td><td> 0</td><td> 0</td><td>r-</td><td>d</td><td> 0</td><td>σι</td><td> 0</td><td>f-</td><td>r-l</td><td> 0</td><td> 0</td><td> 0</td><td>Γ-</td><td></td><td> 0</td><td> 0</td><td> 0</td><td>t-</td><td>tH</td><td> 0</td><td> 0</td>

<td> 1’</td><td></td><td></td><td></td><td>d</td><td>r-l</td><td>Oí</td><td>Oí</td><td>Oí</td><td> 0</td><td> 0</td><td>tí</td><td>tí</td><td>tí</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>id</td><td>id</td><td>id</td><td>rd</td><td>rd</td><td>id</td><td>id</td>

<td> ©</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>d</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td></td><td>id</td><td>Ctí</td><td>(tí</td><td>(tí</td><td>tí</td><td>OJ</td><td>Oí</td><td>m</td><td>d</td><td>tí</td><td>Oí</td><td>(tí</td><td> 0 0</td><td> 0</td><td>OJ</td><td> 05</td><td>rH</td><td>Ctí</td><td>Oí</td><td> 0</td><td>tí</td><td> 0</td><td> 0</td><td> 0</td><td> 0</td><td>id</td><td>&lt;tí</td><td> 0</td><td> 0</td><td>(tí</td><td>OI</td><td>Oí</td><td> 0</td>

<td> 81</td><td>0 σι 0</td><td>O 0 t—1</td><td>tí tí O</td><td> 0 0 0</td><td>O CO 0</td><td>0 0 CO</td><td>0 00 d</td><td>r-l r-l f*</td><td>0 O 0</td><td>co r-l r-</td><td>Γ- ΟΟ 0</td><td> 0 0 0</td><td>tí {tí O</td><td>o r-l 0</td><td>0 0 Oí</td><td>O) 0 Oí</td><td>σι 0 co</td><td>00 00 o</td><td>σι Φ o</td><td>O 0</td><td>0 tí 0</td><td> 0 0 0</td><td>0 tí 0</td><td>O 0 CO</td><td>P- 0 c-</td><td>0 c- O</td><td>t- P- t-</td><td>r~ Oí 0</td><td> 0 0 0</td><td>t- rd tí</td><td>tí 0 0</td><td>O 0 tí</td><td>0 tí tí</td>

<td>i</td><td>p-</td><td>Ó o,</td><td>O °</td><td>O O,</td><td>&lt;—1 O,</td><td>O O,</td><td>O O,</td><td>O</td><td>O o</td><td>o</td><td>δ</td><td>r-l</td><td>δ o.</td><td>O</td><td>O O,</td><td>O °|</td><td>o °,</td><td>o °|</td><td>ó</td><td>O O,</td><td>O O,</td><td>O °|</td><td>O °|</td><td>o °,</td><td>o °|</td><td>O °|</td><td>O °|</td><td>O °|</td><td>O °|</td><td>O °|</td><td>o °|</td><td>O °,</td><td>O °|</td>

<td>SS</td><td>g'</td><td>s</td><td>g</td><td>g</td><td>i¹</td><td>g¹</td><td> §</td><td> §</td><td>g¹</td><td>g'</td><td> §</td><td>g‘</td><td>g</td><td>g'</td><td>g</td><td>g'</td><td>g</td><td>g¹</td><td>g'</td><td>g</td><td>g¹</td><td></td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td>g</td><td></td><td></td>

<td>SÍ ?3 id W TO O</td><td> 1</td><td>i</td><td>a</td><td>d</td><td>g a</td><td>M 0</td><td>d A</td><td> 1</td><td>ffl</td><td> 0</td><td>p- u</td><td>i</td><td>0 A</td><td>tí §</td><td>o</td><td> 1</td><td> 1</td><td>í</td><td> §</td><td>s §</td><td></td><td>s §</td><td> 1</td><td>l</td><td> £ 8</td><td> 0</td><td>g</td><td>w a</td><td>a</td><td>A %</td><td>_g</td><td>i</td><td> 8</td>

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<td>i Cft 8 &lt;0 H ω</td><td>i</td><td> ;</td><td>i</td><td> 1</td><td></td><td></td><td> 1</td><td></td><td>j</td><td></td><td>i</td><td> ¡</td><td> 5</td><td>i</td><td>j</td><td></td><td>i</td><td> 1</td><td></td><td></td><td></td><td>j</td><td></td><td>i</td><td>s</td><td></td><td> 1</td><td></td><td></td><td></td><td> 1</td><td>i</td><td></td><td></td><td></td><td> ¡</td>

<td>a „ gg M</td><td>in H</td><td>&lt;n «tí H</td><td>co tí «-i</td><td>r- tí H</td><td>H 1/1 H</td><td>in ιή H</td><td>&lt;n m H</td><td>ld i—1</td><td>Γ- ΙΟ H</td><td>t- r1</td><td>m Γ- Η</td><td>en Γ- Η</td><td>ftí cO H</td><td>t* oo H</td><td>0&gt; H</td><td>Lfl 91 H</td><td>σι &lt;n H</td><td>o (S</td><td>r- o (S</td><td>H CS</td><td>Lfl H CS</td><td>&lt;n H ÍS</td><td>«tí ÍS ÍS</td><td>c- &lt;s ÍS</td><td>«tí ÍS</td><td>Lfl (tí es</td><td>σι ftí ÍS</td><td>(tí tí cs</td><td>Γ- tí ÍS</td><td>H lfl ÍS</td><td>ifi lfl es</td><td>σι tn ÍS</td><td>ftí LO es</td><td>Γ- ΙΟ ÍS</td><td>H t- CS</td><td>lfl c- es</td>

<td>0 W</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>g</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 1 •8</td><td>i</td><td> |</td><td></td><td> 1</td><td> 1</td><td> 1</td><td>I</td><td> ¡</td><td> 1</td><td>I</td><td>u</td><td> 1</td><td> ¡</td><td> ¡</td><td>I</td><td> !</td><td>h</td><td>j</td><td></td><td></td><td> 1</td><td></td><td>fí</td><td> 1</td><td> ¡</td><td></td><td></td><td></td><td> ¡</td><td></td><td></td><td>j</td><td></td><td></td><td></td><td></td>

<td>w</td><td> 1</td><td> $</td><td>y</td><td></td><td>g</td><td></td><td> 1</td><td>b</td><td></td><td>i</td><td> 8</td><td>y</td><td>fe</td><td>fe</td><td> 8</td><td>i</td><td> 8</td><td>i</td><td></td><td></td><td></td><td>fe</td><td>fe</td><td>b</td><td>i</td><td>fe</td><td> §</td><td>fe</td><td>b</td><td> &amp;</td><td>fe</td><td>g</td><td></td><td>b</td><td>fe</td><td> §</td>

<td>a.. gg</td><td>tí m H</td><td>00 ftí H</td><td>ÍS tí H</td><td>LO tí</td><td>o m H</td><td>tí lfl H</td><td>00 in H</td><td>ÍS LO H</td><td>LD LO</td><td>o Γ- Η</td><td>tí Γ- Η</td><td>00 Γ- Η</td><td>ÍS 00 H</td><td>LO OO H</td><td>O en H</td><td>tí tn H</td><td>αθ «n H</td><td>fS O (S</td><td>LO O ÍN</td><td>o H (S</td><td>tí H ÍS</td><td>00 H CS</td><td>ÍS ÍS es</td><td>10 ÍS &lt;s</td><td>o ftí ÍS</td><td>tí «tí cs</td><td>00 ftí es</td><td>(S tí es</td><td>LO tí (S</td><td>o lfl es</td><td>tí lfl es</td><td>00 lfl cs</td><td>es LD es</td><td>LO LO &lt;s</td><td>o c- es</td><td>tí í- es</td>

<td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> 3</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td> 1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> •8</td><td></td><td>i</td><td> 1</td><td></td><td> ¡</td><td> |</td><td>l</td><td> 1</td><td>i</td><td> 1</td><td> 1</td><td>S</td><td>H</td><td>j</td><td>j</td><td>i</td><td> 5</td><td> 1</td><td></td><td> ¡</td><td> !</td><td>I</td><td> !</td><td>i</td><td></td><td></td><td> 1</td><td>g</td><td>i</td><td></td><td> 1</td><td>i</td><td>s</td><td></td><td></td><td>i</td>

<td>¡Ϊ h</td><td> 1</td><td> 1</td><td>I</td><td> 1</td><td>I</td><td>l</td><td>i</td><td> §</td><td> §</td><td> !</td><td>I</td><td> 1</td><td>i</td><td> ¡</td><td>i</td><td>S</td><td>i</td><td> !</td><td>b</td><td> 1</td><td>i</td><td></td><td>S</td><td>I</td><td></td><td>I</td><td></td><td>Ϊ</td><td>Ϊ</td><td> ¡</td><td></td><td> 1</td><td></td><td> 1</td><td>s</td><td></td>

<td>a.. o_a</td><td>h m</td><td>r- m</td><td>H tí</td><td>lfl tí</td><td>&lt;n tí</td><td>(tí m</td><td>r- LO</td><td>(—« LO</td><td>in LO</td><td>&lt;n ID</td><td>«tí r*</td><td>c- c-</td><td>H 00</td><td>lfl co</td><td>&lt;n co</td><td>«tí σι</td><td>σι</td><td>o</td><td>Lfl O</td><td>σι o</td><td>«tí H</td><td>Γ- Η</td><td>ÍS</td><td>Lfl ÍS</td><td>σι ÍS</td><td>(tí «tí</td><td>Γ- Η</td><td>tí</td><td>lfl tí</td><td>en tí</td><td>(tí lfl</td><td>t- *n</td><td>H LO</td><td>Lfl LO</td><td>σι VJ</td><td>ftí</td>

<td>S » 0)</td><td>H</td><td>H</td><td>H</td><td>c·1</td><td>H</td><td>H</td><td>H</td><td>H</td><td>i-1</td><td>H</td><td>H</td><td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td> «1</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td>H</td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td>

<td>•s-3</td><td>&lt;S ÍS &lt;n en</td><td>(S t- r-</td><td>CS ιή r·1 es</td><td>ÍS O LO tí</td><td>tí 00 lD tí</td><td>CS LO fS O</td><td>fS CS lfl «S</td><td>Γ1 Lfl Γ- ΙΟ</td><td>tí en o o</td><td>tí t— es</td><td>i—1 Γ- Γ- Η</td><td>H H LO lfl</td><td>ÍS co tí co</td><td>tí LO CS H</td><td>H co H LO</td><td>H (— &lt;n in CJ</td><td>H 00 c- H</td><td>ÍS tí oo H</td><td>H (S &lt;n</td><td>H LO O ÍS</td><td>fS có ÍS CS «s</td><td>(tí H lfl lfl lfl</td><td>(S ifi t- es &lt;s</td><td>ÍS tí ÍS tí o</td><td>H 00 fS cs o</td><td>H LO O «tí fS</td><td>ÍS O tí &lt;n lfl</td><td>H LO LO tí rs</td><td>cs &lt;n σι lfl LO</td><td>es o &lt;n o</td><td>es η o o [-</td><td>σι es o</td><td>ftí ftí H t- «tí</td><td>H O co tí es</td><td>H Γ- Η í- es</td><td>H t- &lt;n &lt;n ÍS</td>

<td>Θ w</td><td>o</td><td>o</td><td>tn</td><td>o ¡'</td><td>o i¹</td><td>o</td><td>o I¹</td><td>H 1'</td><td>o l¹</td><td>o i¹</td><td>O i¹</td><td>O i'</td><td>o l¹</td><td>O i</td><td>O J</td><td>o i¹</td><td>O</td><td>O</td><td>o i</td><td>O i¹</td><td>o í</td><td>O</td><td>o 1'</td><td>o</td><td>i</td><td> 1</td><td>i'</td><td> 1</td><td></td><td>s'</td><td>í</td><td>í</td><td>O í</td><td>Ϊ'</td><td>í</td><td>l¹</td>

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