Patent Publication Number: US-2003232442-A1

Title: Antisense modulation of PAZ/PIWI domain-containing protein expression

Description:
FIELD OF THE INVENTION  
       [0001] The present invention provides compositions and methods for modulating the expression of PAZ/PIWI domain-containing protein. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding PAZ/PIWI domain-containing protein. Such compounds have been shown to modulate the expression of PAZ/PIWI domain-containing protein.  
       BACKGROUND OF THE INVENTION  
       [0002] In eukaryotes, protein synthesis involves a complex series of protein and nucleic acid interactions that lead to the assembly of an 80S ribosomal nucleoprotein complex, comprising the methionyl initiator tRNA (Met-tRNA i ) base paired with the initiation codon of a messenger RNA, and result in translation of the mRNA into protein. This process of translation initiation has several linked stages that require the participation of numerous proteins known as eukaryotic translation initiation factors (eIFs). The first stage involves the association of eukaryotic translation initiation factor 2 (eIF-2), GTP nucleotide, and the initiator Met-tRNA i  to form a ternary complex, which then binds to the 40S ribosomal subunit to form a 43S preinitiation complex. In the second stage, the 43S preinitiation complex associates with other eIFs and with the mRNA, while the third stage involves movement of the 43S complex along the mRNA, scanning for the initiation codon, and formation of the 48S initiation complex when the anticodon of the initiator Met-tRNA i  base pairs with the initiation codon. Finally, in the fourth stage, several factors dissociate from the 48S complex, allowing the 60S ribosomal subunit to bind and form an 80S ribosome in a translation-competent initiation complex (Pestova et al.,  Proc. Natl. Acad. Sci. U. S. A.,  2001, 98, 7029-7036).  
       [0003] The gene encoding PAZ/PIWI domain-containing protein (also known as hypothetical protein FLJ12765) has been noted to bear homology to the eukaryotic translation initiation factor EIF2C and  Rattus norvegicus  GERp95 mRNAs, members of a family of genes that encode proteins with PIWI and/or PAZ domains believed to be involved in post-transcriptional gene silencing (PTGS). The eukaryotic translation initiation factor 2C, 1 (EIF2C1) protein promotes the AUG-directed binding of the initiator Met-tRNA i  to 40S ribosomes by stabilizing the formation of the translation initiation eIF-2/Met-tRNA i /GTP ternary complex and promoting guanine nucleotide exchange. The EIF2C1 gene is a member of an evolutionarily conserved multigene family in humans that includes several genes related to the Q99 gene exhibiting increased expression in tumors harboring a mutation in the Wilms tumor suppressor gene WT1. Human EIF2C1 has significant homology to the ARGONAUTE1 (AGO1) gene important for proper development of leaves and cotyledons in  Arabidopsis thaliana  as well as to a gene, F48F7.1, identified in the course of the  Caenorhabditis elegans  genome sequencing project (Koesters et al.,  Genomics,  1999, 61, 210-218). Based on its homology to the EIF2C1/AG01/Q99 family of proteins, the PAZ/PIWI domain-containing protein may also be associated with human cancers.  
       [0004] The rat GERp95 (Golgi ER protein 95 kDa) protein was identified as a Golgi complex and/or endoplasmic reticulum (ER) membrane-associated protein. Numerous GERp95 homologues were noted to occur in a wide range of multicellular organisms, and in particular, GERp95 was noted to be 93.5% identical to the protein encoded by the rabbit homolog of EIF2C1. A technique called double-stranded RNA-induced gene silencing, or RNA interference (RNAi) was used to generate a GERp95-null phenotype in  C. elegans  and show that the  C. elegans  GERp95 orthologue is important for maturation of germ-line stem cells in the gonad of the nematode (Cikaluk et al.,  Mol. Biol. Cell,  1999, 10, 3357-3372). Subsequently, the GERp95 protein was observed to engage an Hsp90 molecular chaperone protein complex prior to its association with intracellular membranes. Hsp90 is an abundant chaperone protein with a limited number of substrate types, most of which are signaling proteins that include protein kinases, steroid hormone receptors, nitric-oxide synthases, and telomerase. Furthermore, the Hsp90 protein was required for the stability and Golgi localization of GERp95 in NRK rat kidney cells. Gerp95 and related proteins were, therefore, predicted to comprise a new class of Hsp90 substrates involved in novel signaling pathways (Tahbaz et al.,  J. Biol. Chem.,  2001, 276, 43294-43299). Thus, a family of highly conserved signal-transducing proteins has been defined and its members are predicted to have roles in regulation of cellular differentiation, development, fertility and gametogenesis, and PTGS (Cikaluk et al.,  Mol. Biol. Cell,  1999, 10, 3357-3372; Tahbaz et al.,  J. Biol. Chem.,  2001, 276, 43294-43299).  
       [0005] The gene encoding PAZ/PIWI domain-containing protein appears to be a member of this multigene family. Within this family, the proteins PIWI (from  Drosophila melanogaster ), AGO1 and Zwille (from  A. thaliana ), were seminal members, and thus, the name PAZ domain was given to the region of homology these proteins share. The PIWI domain has been defined as a 300-amino acid domain that typically occurs C-terminal to the PAZ domain of proteins that contain both domains. PAZ-domain-only and PIWI domain only proteins have also been discovered. The exact function of these domains remains unknown but the proteins containing them are believed to be important in mechanisms of cell fate determination, development and gene silencing (Cerutti et al.,  Trends Biochem. Sci.,  2000, 25, 481-482). Interestingly, the processes of PTGS/RNAi and development have been partially uncoupled in hypomorphic mutants of the AGO1 gene. PTGS was observed to be more sensitive than development to mutations in AGO1, indicating that some members of the PAZ/PIWI domain-containing protein family may have independent functions in these two processes, or that expression levels can differentially affect the two processes. Furthermore, it has been suggested that members of the PAZ/PIWI domain-containing protein family may have partially redundant or non-redundant functions (Morel et al.,  Plant Cell,  2002, 14, 629-639).  
       [0006] In addition to being a potent technique used to generate phenocopies of the null phenotype in the nematode, RNAi is also a natural biological defense used by various organisms to prevent viral replication and infection as well as to silence transposon hopping in the germline. When double-stranded RNA (dsRNA) corresponding to the sense and antisense sequence of an endogenous mRNA is introduced into a cell, it mediates sequence-specific genetic interference, and the cognate mRNA is degraded and the gene silenced (Bass,  Cell,  2000, 101, 235-238; Montgomery and Fire,  Trends Genet.,  1998, 14, 255-258). Because PAZ/PIWI domain-containing protein is also homologous to rde-1 in  C. elegans , and rde-1 mutants completely lack an interference response, PAZ/PIWI domain-containing proteins are implicated in the RNAi mechanism (Morel et al.,  Plant Cell,  2002, 14, 629-639).  
       [0007] Cellular compartmentalization by the Golgi and ER is believed to increase the efficiencies of cellular processes by controlling the spatial and temporal interactions of proteins, nucleic acids, and lipids, and it is now clear from studies of EIF2C1 (GERp95) in  C. elegans , that these two organelles are directly involved in processes that affect cellular differentiation. Mistargeting and/or altered expression of intracellular membrane-associated proteins has been shown previously to have profound effects on cell growth, morphology, and tumorigenicity, and cellular defects in the Golgi or ER underlie the pathophysiology of many human diseases such as familial hypercholesterolemia, polycystic kidney disease, Tangier disease, cystic fibrosis, mucopolysaccharidosis types I, IV, and VII, progeroid syndrome, and many others. Several alternative mechanisms have been proposed for regulation of the activity and localization of the GERp95 protein in rat cells. One possibility is that there are cell-specific isoforms of this protein. Postranslational modifications have also been proposed as a means of regulating subcellular localization or activity. It has also been proposed that GERp95 may be displaced from the translation initiation complex by the interfering dsRNA, directly preventing its activity in the translation of a target mRNA (Cikaluk et al.,  Mol. Biol. Cell,  1999, 10, 3357-3372). Based on its structural homology, PAZ/PIWI domain-containing protein may be similarly regulated by the existence of cell-specific isoforms, splice variants, posttranslational modifications or compartmentalization and have different activities, possibly involved in the control of mRNA translation and/or RNAi.  
       [0008] Thus, PAZ/PIWI domain-containing protein is a potential therapeutic target in conditions involving aberrant function of translation initiation complexes or leading to altered gene expression, as well as in conditions resulting from mistargeting, compartmentalization, or misregulation of signaling pathways by the PAZ/PIWI domain-containing protein and dysregulation of stem cell differentiation. PAZ/PIWI domain-containing protein is also a target potentially allowing for further elucidation of the mechanisms of RNAi.  
       [0009] Disclosed and claimed in PCT Publication WO 01/02568 is a library of polynucleotides, the library comprising the sequence information of at least one of a group of nucleotide sequences, wherein one member of said group bears a region of identity to 370 nucleotides of the gene encoding PAZ/PIWI domain-containing protein (nucleotides 1270-1639 of GenBank Accession NM — 024852.1). Further claimed is an isolated polynucleotide comprising a nucleotide sequence having at least 90% sequence identity to an identifying sequence of said group or a degenerate variant or fragment thereof, a recombinant host cell containing the polynucleotide, an isolated polypeptide encoded by the polynucleotide, an antibody that specifically binds said polypeptide, and a vector comprising said polynucleotide. Antisense oligonucleotides are generally disclosed (Williams et al., 2001).  
       [0010] Disclosed and claimed in PCT Publication WO 01/77164 is a nucleic acid comprising a sequence at least 18 bases in length of a segment of the chemically pretreated DNA of genes associated with metabolism taken from a group of sequences in which a member of said group bears a region of identity to 20 nucleotides of the gene encoding PAZ/PIWI domain-containing protein (nucleotides 1491-1510 of GenBank Accession NM — 024852.1) as well as sequences complementary thereto. Further claimed is an oligonucleotide or peptide nucleic acid (PNA)-oligomer comprising a sequence having a length of at least 9 nucleotides which hybridizes to or is identical to a chemically pretreated DNA of said genes associated with metabolism, a set of said oligomers, use of a set of oligomer probes comprising at least ten of said oligomers for detecting the cytosine methylation state and/or single nucleotide polymorphisms (SNPs) in a chemically pretreated genomic DNA, a method for manufacturing an array of different oligomers fixed to a carrier material for analyzing diseases associated with the methylation state of the CpG dinucleotides, a method for ascertaining genetic and/or epigenetic parameters for the diagnosis and/or therapy of existing diseases or the predisposition to specific diseases by analyzing cytosine methylations, a kit comprising a bisulfite reagent as well as oligonucleotides and/or PNA-oligomers, and the use of said nucleic acid for the diagnosis of metabolic disease, solid tumours and cancers (Olek et al., 2001).  
       [0011] Currently, there are no known therapeutic agents which effectively inhibit the synthesis of PAZ/PIWI domain-containing protein.  
       [0012] Consequently, there remains a long felt need for agents capable of effectively inhibiting PAZ/PIWI domain-containing protein function.  
       [0013] Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of PAZ/PIWI domain-containing protein expression.  
       [0014] The present invention provides compositions and methods for modulating PAZ/PIWI domain-containing protein expression.  
       SUMMARY OF THE INVENTION  
       [0015] The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding PAZ/PIWI domain-containing protein, and which modulate the expression of PAZ/PIWI domain-containing protein. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of PAZ/PIWI domain-containing protein in cells or tissues comprising contacting said cells or tissues with one or more of the antisense compounds or compositions of the invention. Further provided are methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of PAZ/PIWI domain-containing protein by administering a therapeutically or prophylactically effective amount of one or more of the antisense compounds or compositions of the invention.  
       DETAILED DESCRIPTION OF THE INVENTION  
       [0016] The present invention employs oligomeric compounds, particularly antisense oligonucleotides, for use in modulating the function of nucleic acid molecules encoding PAZ/PIWI domain-containing protein, ultimately modulating the amount of PAZ/PIWI domain-containing protein produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding PAZ/PIWI domain-containing protein. As used herein, the terms “target nucleic acid” and “nucleic acid encoding PAZ/PIWI domain-containing protein” encompass DNA encoding PAZ/PIWI domain-containing protein, RNA (including pre-mRNA and mRNA) transcribed from such DNA, and also cDNA derived from such RNA. The specific hybridization of an oligomeric compound with its target nucleic acid interferes with the normal function of the nucleic acid. This modulation of function of a target nucleic acid by compounds which specifically hybridize to it is generally referred to as “antisense”. The functions of DNA to be interfered with include replication and transcription. The functions of RNA to be interfered with include all vital functions such as, for example, translocation of the RNA to the site of protein translation, translocation of the RNA to sites within the cell which are distant from the site of RNA synthesis, translation of protein from the RNA, splicing of the RNA to yield one or more mRNA species, and catalytic activity which may be engaged in or facilitated by the RNA. The overall effect of such interference with target nucleic acid function is modulation of the expression of PAZ/PIWI domain-containing protein. In the context of the present invention, “modulation” means either an increase (stimulation) or a decrease (inhibition) in the expression of a gene. In the context of the present invention, inhibition is the preferred form of modulation of gene expression and mRNA is a preferred target.  
       [0017] It is preferred to target specific nucleic acids for antisense. “Targeting” an antisense compound to a particular nucleic acid, in the context of this invention, is a multistep process. The process usually begins with the identification of a nucleic acid sequence whose function is to be modulated. This may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target is a nucleic acid molecule encoding PAZ/PIWI domain-containing protein. The targeting process also includes determination of a site or sites within this gene for the antisense interaction to occur such that the desired effect, e.g., detection or modulation of expression of the protein, will result. Within the context of the present invention, a preferred intragenic site is the region encompassing the translation initiation or termination codon of the open reading frame (ORF) of the gene. Since, as is known in the art, the translation initiation codon is typically 5′-AUG (in transcribed mRNA molecules; 5′-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the “AUG codon,” the “start codon” or the “AUG start codon”. A minority of genes have a translation initiation codon having the RNA sequence 5′-GUG, 5′-UUG or 5′-CUG, and 5′-AUA, 5′-ACG and 5′-CUG have been shown to function in vivo. Thus, the terms “translation initiation codon” and “start codon” can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, “start codon” and “translation initiation codon” refer to the codon or codons that are used in vivo to initiate translation of an mRNA molecule transcribed from a gene encoding PAZ/PIWI domain-containing protein, regardless of the sequence(s) of such codons.  
       [0018] It is also known in the art that a translation termination codon (or “stop codon”) of a gene may have one of three sequences, i.e., 5′-UAA, 5′-UAG and 5′-UGA (the corresponding DNA sequences are 5′-TAA, 5′-TAG and 5′-TGA, respectively). The terms “start codon region” and “translation initiation codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′ or 3′) from a translation initiation codon. Similarly, the terms “stop codon region” and “translation termination codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′ or 3′) from a translation termination codon.  
       [0019] The open reading frame (ORF) or “coding region,” which is known in the art to refer to the region between the translation initiation codon and the translation termination codon, is also a region which may be targeted effectively. Other target regions include the 5′ untranslated region (5′UTR), known in the art to refer to the portion of an mRNA in the 5′ direction from the translation initiation codon, and thus including nucleotides between the 5′ cap site and the translation initiation codon of an mRNA or corresponding nucleotides on the gene, and the 3′ untranslated region (3′UTR), known in the art to refer to the portion of an mRNA in the 3′ direction from the translation termination codon, and thus including nucleotides between the translation termination codon and 3′ end of an mRNA or corresponding nucleotides on the gene. The 5′ cap of an mRNA comprises an N7-methylated guanosine residue joined to the 5′-most residue of the mRNA via a 5′-5′ triphosphate linkage. The 5′ cap region of an mRNA is considered to include the 5′ cap structure itself as well as the first 50 nucleotides adjacent to the cap. The 5′ cap region may also be a preferred target region.  
       [0020] Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions, known as “introns,” which are excised from a transcript before it is translated. The remaining (and therefore translated) regions are known as “exons” and are spliced together to form a continuous mRNA sequence. mRNA splice sites, i.e., intron-exon junctions, may also be preferred target regions, and are particularly useful in situations where aberrant splicing is implicated in disease, or where an overproduction of a particular mRNA splice product is implicated in disease. Aberrant fusion junctions due to rearrangements or deletions are also preferred targets. mRNA transcripts produced via the process of splicing of two (or more) mRNAs from different gene sources are known as “fusion transcripts”. It has also been found that introns can be effective, and therefore preferred, target regions for antisense compounds targeted, for example, to DNA or pre-mRNA.  
       [0021] It is also known in the art that alternative RNA transcripts can be produced from the same genomic region of DNA. These alternative transcripts are generally known as “variants”. More specifically, “pre-mRNA variants” are transcripts produced from the same genomic DNA that differ from other transcripts produced from the same genomic DNA in either their start or stop position and contain both intronic and extronic regions.  
       [0022] Upon excision of one or more exon or intron regions or portions thereof during splicing, pre-mRNA variants produce smaller “mRNA variants”. Consequently, mRNA variants are processed pre-mRNA variants and each unique pre-mRNA variant must always produce a unique mRNA variant as a result of splicing. These mRNA variants are also known as “alternative splice variants”. If no splicing of the pre-mRNA variant occurs then the pre-mRNA variant is identical to the mRNA variant.  
       [0023] It is also known in the art that variants can be produced through the use of alternative signals to start or stop transcription and that pre-mRNAs and mRNAs can possess more that one start codon or stop codon. Variants that originate from a pre-mRNA or mRNA that use alternative start codons are known as “alternative start variants” of that pre-mRNA or mRNA. Those transcripts that use an alternative stop codon are known as “alternative stop variants” of that pre-mRNA or mRNA. One specific type of alternative stop variant is the “polyA variant” in which the multiple transcripts produced result from the alternative selection of one of the “polyA stop signals” by the transcription machinery, thereby producing transcripts that terminate at unique polyA sites.  
       [0024] Once one or more target sites have been identified, oligonucleotides are chosen which are sufficiently complementary to the target, i.e., hybridize sufficiently well and with sufficient specificity, to give the desired effect.  
       [0025] In the context of this invention, “hybridization” means hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases. For example, adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bonds. “Complementary,” as used herein, refers to the capacity for precise pairing between two nucleotides. For example, if a nucleotide at a certain position of an oligonucleotide is capable of hydrogen bonding with a nucleotide at the same position of a DNA or RNA molecule, then the oligonucleotide and the DNA or RNA are considered to be complementary to each other at that position. The oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding positions in each molecule are occupied by nucleotides which can hydrogen bond with each other. Thus, “specifically hybridizable” and “complementary” are terms which are used to indicate a sufficient degree of complementarity or precise pairing such that stable and specific binding occurs between the oligonucleotide and the DNA or RNA target. It is understood in the art that the sequence of an antisense compound need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable.  
       [0026] An antisense compound is specifically hybridizable when binding of the compound to the target DNA or RNA molecule interferes with the normal function of the target DNA or RNA to cause a loss of activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, and in the case of in vitro assays, under conditions in which the assays are performed. It is preferred that the antisense compounds of the present invention comprise at least 80% sequence complementarity to a target region within the target nucleic acid, moreover that they comprise 90% sequence complementarity and even more comprise 95% sequence complementarity to the target region within the target nucleic acid sequence to which they are targeted. For example, an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary, and would therefore specifically hybridize, to a target region would represent 90 percent complementarity. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined routinely using basic local alignment search tools (BLAST programs) (Altschul et al.,  J. Mol. Biol.,  1990, 215, 403-410; Zhang and Madden,  Genome Res.,  1997, 7, 649-656).  
       [0027] Antisense and other compounds of the invention, which hybridize to the target and inhibit expression of the target, are identified through experimentation, and representative sequences of these compounds are hereinbelow identified as preferred embodiments of the invention. The sites to which these preferred antisense compounds are specifically hybridizable are hereinbelow referred to as “preferred target regions” and are therefore preferred sites for targeting. As used herein the term “preferred target region” is defined as at least an 8-nucleobase portion of a target region to which an active antisense compound is targeted. While not wishing to be bound by theory, it is presently believed that these target regions represent regions of the target nucleic acid which are accessible for hybridization.  
       [0028] While the specific sequences of particular preferred target regions are set forth below, one of skill in the art will recognize that these serve to illustrate and describe particular embodiments within the scope of the present invention. Additional preferred target regions may be identified by one having ordinary skill.  
       [0029] Target regions 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative preferred target regions are considered to be suitable preferred target regions as well.  
       [0030] Exemplary good preferred target regions include DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred target regions (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately upstream of the 5′-terminus of the target region and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). Similarly good preferred target regions are represented by DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred target regions (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately downstream of the 3′-terminus of the target region and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). One having skill in the art, once armed with the empirically-derived preferred target regions illustrated herein will be able, without undue experimentation, to identify further preferred target regions. In addition, one having ordinary skill in the art will also be able to identify additional compounds, including oligonucleotide probes and primers, that specifically hybridize to these preferred target regions using techniques available to the ordinary practitioner in the art.  
       [0031] Antisense compounds are commonly used as research reagents and diagnostics. For example, antisense oligonucleotides, which are able to inhibit gene expression with exquisite specificity, are often used by those of ordinary skill to elucidate the function of particular genes. Antisense compounds are also used, for example, to distinguish between functions of various members of a biological pathway. Antisense modulation has, therefore, been harnessed for research use.  
       [0032] For use in kits and diagnostics, the antisense compounds of the present invention, either alone or in combination with other antisense compounds or therapeutics, can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of a portion or the entire complement of genes expressed within cells and tissues.  
       [0033] Expression patterns within cells or tissues treated with one or more antisense compounds are compared to control cells or tissues not treated with antisense compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined. These analyses can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.  
       [0034] Examples of methods of gene expression analysis known in the art include DNA arrays or microarrays (Brazma and Vilo,  FEBS Lett.,  2000, 480, 17-24; Celis, et al.,  FEBS Lett.,  2000, 480, 2-16), SAGE (serial analysis of gene expression) (Madden, et al.,  Drug Discov. Today,  2000, 5, 415-425), READS (restriction enzyme amplification of digested cDNAs) (Prashar and Weissman,  Methods Enzymol.,  1999, 303, 258-72), TOGA (total gene expression analysis) (Sutcliffe, et al.,  Proc. Natl. Acad. Sci. U. S. A.,  2000, 97, 1976-81), protein arrays and proteomics (Celis, et al.,  FEBS Lett.,  2000, 480, 2-16; Jungblut, et al.,  Electrophoresis,  1999, 20, 2100-10), expressed sequence tag (EST) sequencing (Celis, et al.,  FEBS Lett.,  2000, 480, 2-16; Larsson, et al.,  J. Biotechnol.,  2000, 80, 143-57), subtractive RNA fingerprinting (SuRF) (Fuchs, et al.,  Anal. Biochem.,  2000, 286, 91-98; Larson, et al.,  Cytometry,  2000, 41, 203-208), subtractive cloning, differential display (DD) (Jurecic and Belmont,  Curr. Opin. Microbiol.,  2000, 3, 316-21), comparative genomic hybridization (Carulli, et al.,  J. Cell Biochem. Suppl.,  1998, 31, 286-96), FISH (fluorescent in situ hybridization) techniques (Going and Gusterson,  Eur. J. Cancer,  1999, 35, 1895-904) and mass spectrometry methods (reviewed in To,  Comb. Chem. High Throughput Screen,  2000, 3, 235-41).  
       [0035] The specificity and sensitivity of antisense is also harnessed by those of skill in the art for therapeutic uses. Antisense oligonucleotides have been employed as therapeutic moieties in the treatment of disease states in animals and man. Antisense oligonucleotide drugs, including ribozymes, have been safely and effectively administered to humans and numerous clinical trials are presently underway. It is thus established that oligonucleotides can be useful therapeutic modalities that can be configured to be useful in treatment regimes for treatment of cells, tissues and animals, especially humans.  
       [0036] In the context of this invention, the term “oligonucleotide” refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics thereof. This term includes oligonucleotides composed of naturally-occurring nucleobases, sugars and covalent internucleoside (backbone) linkages as well as oligonucleotides having non-naturally-occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target and increased stability in the presence of nucleases.  
       [0037] While antisense oligonucleotides are a preferred form of antisense compound, the present invention comprehends other oligomeric antisense compounds, including but not limited to oligonucleotide mimetics such as are described below. The antisense compounds in accordance with this invention preferably comprise from about 8 to about 80 nucleobases (i.e. from about 8 to about 80 linked nucleosides). Particularly preferred antisense compounds are antisense oligonucleotides from about 8 to about 50 nucleobases, even more preferably those comprising from about 12 to about 30 nucleobases. Antisense compounds include ribozymes, external guide sequence (EGS) oligonucleotides (oligozymes), and other short catalytic RNAs or catalytic oligonucleotides which hybridize to the target nucleic acid and modulate its expression.  
       [0038] Antisense compounds 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative antisense compounds are considered to be suitable antisense compounds as well.  
       [0039] Exemplary preferred antisense compounds include DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately upstream of the 5′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). Similarly preferred antisense compounds are represented by DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately downstream of the 3′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). One having skill in the art, once armed with the empirically-derived preferred antisense compounds illustrated herein will be able, without undue experimentation, to identify further preferred antisense compounds.  
       [0040] Antisense and other compounds of the invention, which hybridize to the target and inhibit expression of the target, are identified through experimentation, and representative sequences of these compounds are herein identified as preferred embodiments of the invention. While specific sequences of the antisense compounds are set forth herein, one of skill in the art will recognize that these serve to illustrate and describe particular embodiments within the scope of the present invention. Additional preferred antisense compounds may be identified by one having ordinary skill.  
       [0041] As is known in the art, a nucleoside is a base-sugar combination. The base portion of the nucleoside is normally a heterocyclic base. The two most common classes of such heterocyclic bases are the purines and the pyrimidines. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to either the 2′, 3′ or 5′ hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. In turn, the respective ends of this linear polymeric structure can be further joined to form a circular structure, however, open linear structures are generally preferred. In addition, linear structures may also have internal nucleobase complementarity and may therefore fold in a manner as to produce a double stranded structure. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the internucleoside backbone of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3′ to 5′ phosphodiester linkage.  
       [0042] Specific examples of preferred antisense compounds useful in this invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. As defined in this specification, oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides.  
       [0043] Preferred modified oligonucleotide backbones include, for example, phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates, 5′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, selenophosphates and boranophosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein one or more internucleotide linkages is a 3′ to 3′, 5′ to 5′ or 2′ to 2′ linkage. Preferred oligonucleotides having inverted polarity comprise a single 3′ to 3′ linkage at the 3′-most internucleotide linkage i.e. a single inverted nucleoside residue which may be abasic (the nucleobase is missing or has a hydroxyl group in place thereof). Various salts, mixed salts and free acid forms are also included.  
       [0044] Representative United States patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,194,599; 5,565,555; 5,527,899; 5,721,218; 5,672,697 and 5,625,050, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.  
       [0045] Preferred modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; riboacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH 2  component parts.  
       [0046] Representative United States patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos. 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; 5,792,608; 5,646,269 and 5,677,439, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.  
       [0047] In other preferred oligonucleotide mimetics, both the sugar and the internucleoside linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base units are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al.,  Science,  1991, 254, 1497-1500.  
       [0048] Most preferred embodiments of the invention are oligonucleotides with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular —CH 2 —NH—O—CH 2 —, —CH 2 —N(CH 3 )—O—CH 2 — [known as a methylene (methylimino) or MMI backbone], —CH 2 —O—N(CH 3 )—CH 2 —, —CH 2 —N(CH 3 )—N(CH 3 )—CH 2 — and —O—N(CH 3 )—CH 2 —CH 2 — [wherein the native phosphodiester backbone is represented as —O—P—O—CH 2 —] of the above referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above referenced U.S. Pat. No. 5,602,240. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506.  
       [0049] Modified oligonucleotides may also contain one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following at the 2′ position: OH; F; O—, S—, or N-alkyl; O—, S—, or N-alkenyl; O—, S— or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C 1  to C 10 alkyl or C 2  to C 10  alkenyl and alkynyl. Particularly preferred are O[(CH 2 ) n O] m CH 3 , O(CH 2 ) n OCH 3 , O(CH 2 ) n NH 2 , O(CH 2 ) n CH 3 , O(CH 2 ) n ONH 2 , and O(CH 2 ) n ON[(CH 2 ) n CH 3 ] 2 , where n and m are from 1 to about 10. Other preferred oligonucleotides comprise one of the following at the 2′ position: C 1  to C 10  lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF3, OCF 3 , SOCH 3 , SO 2 CH 3 . ONO 2 , NO 2 , N 3 , NH 2 , heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2′-methoxyethoxy (2′-O—CH 2 CH 2 OCH 3 , also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al.,  Helv. Chim. Acta,  1995, 78, 486-504) i.e., an alkoxyalkoxy group. A further preferred modification includes 2′-dimethylaminooxyethoxy, i.e., a O(CH 2 ) 2 ON(CH 3 ) 2  group, also known as 2′-DMAOE, as described in examples hereinbelow, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethyl-amino-ethoxy-ethyl or 2′-DMAEOE), i.e., 2′-O—CH 2 —O—CH 2 —N(CH 3 ) 2 , also described in examples hereinbelow.  
       [0050] Other preferred modifications include 2′-methoxy (2′-O—CH 3 ), 2′-aminopropoxy (2′-OCH 2 CH 2 CH 2 NH 2 ), 2′-allyl (2′-CH 2 —CH═CH 2 ), 2′-O-allyl (2′-O—CH 2 —CH═CH 2 ) and 2′-fluoro (2′-F). The 2′-modification may be in the arabino (up) position or ribo (down) position. A preferred 2′-arabino modification is 2′-F. Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides and the 5′ position of 5′ terminal nucleotide. Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,792,747; and 5,700,920, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.  
       [0051] A further preferred modification includes Locked Nucleic Acids (LNAs) in which the 2′-hydroxyl group is linked to the 3′ or 4′ carbon atom of the sugar ring thereby forming a bicyclic sugar moiety. The linkage is preferably a methelyne (—CH 2 —) n  group bridging the 2′ oxygen atom and the 4′ carbon atom wherein n is 1 or 2. LNAs and preparation thereof are described in WO 98/39352 and WO 99/14226.  
       [0052] Oligonucleotides may also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (—C≡C—CH 3 ) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further modified nucleobases include tricyclic pyrimidines such as phenoxazine cytidine (1H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), phenothiazine cytidine (1H-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps such as a substituted phenoxazine cytidine (e.g. 9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), carbazole cytidine (2H-pyrimido[4,5-b]indol-2-one), pyridoindole cytidine (H-pyrido[3′,2′:4,5]pyrrolo[2,3-d]pyrimidin-2-one). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in  The Concise Encyclopedia Of Polymer Science And Engineering,  pages 858-859, Kroschwitz, J. I., ed. John Wiley &amp; Sons, 1990, those disclosed by Englisch et al.,  Angewandte Chemie,  International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y. S., Chapter 15 , Antisense Research and Applications,  pages 289-302, Crooke, S. T. and Lebleu, B. ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. (Sanghvi, Y. S., Crooke, S. T. and Lebleu, B., eds.,  Antisense Research and Applications,  CRC Press, Boca Raton, 1993, pp. 276-278) and are presently preferred base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications.  
       [0053] Representative United States patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Pat. No. 3,687,808, as well as U.S. Pat Nos. 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,645,985; 5,830,653; 5,763,588; 6,005,096; and 5,681,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, which is commonly owned with the instant application and also herein incorporated by reference.  
       [0054] Another modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. The compounds of the invention can include conjugate groups covalently bound to functional groups such as primary or secondary hydroxyl groups. Conjugate groups of the invention include intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligomers, and groups that enhance the pharmacokinetic properties of oligomers. Typical conjugate groups include cholesterols, lipids, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluoresceins, rhodamines, coumarins, and dyes. Groups that enhance the pharmacodynamic properties, in the context of this invention, include groups that improve oligomer uptake, enhance oligomer resistance to degradation, and/or strengthen sequence-specific hybridization with RNA. Groups that enhance the pharmacokinetic properties, in the context of this invention, include groups that improve oligomer uptake, distribution, metabolism or excretion. Representative conjugate groups are disclosed in International Patent Application PCT/US92/09196, filed Oct. 23, 1992 the entire disclosure of which is incorporated herein by reference. Conjugate moieties include but are not limited to lipid moieties such as a cholesterol moiety (Letsinger et al.,  Proc. Natl. Acad. Sci. USA,  1989, 86, 6553-6556), cholic acid (Manoharan et al.,  Bioorg. Med. Chem. Let.,  1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al.,  Ann. N.Y. Acad. Sci.,  1992, 660, 306-309; Manoharan et al.,  Bioorg. Med. Chem. Let.,  1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al.,  Nucl. Acids Res.,  1992, 20, 533-538), an aliphatic chain, e.g., dodecandiol or undecyl residues (Saison-Behmoaras et al.,  EMBO J.,  1991, 10, 1111-1118; Kabanov et al.,  FEBS Lett.,  1990, 259, 327-330; Svinarchuk et al.,  Biochimie,  1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al.,  Tetrahedron Lett.,  1995, 36, 3651-3654; Shea et al.,  Nucl. Acids Res.,  1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al.,  Nucleosides  &amp;  Nucleotides,  1995, 14, 969-973), or adamantane acetic acid (Manoharan et al.,  Tetrahedron Lett.,  1995, 36, 3651-3654), a palmityl moiety (Mishra et al.,  Biochim. Biophys. Acta,  1995, 1264, 229-237), or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al.,  J. Pharmacol. Exp. Ther.,  1996, 277, 923-937). Oligonucleotides of the invention may also be conjugated to active drug substances, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indomethicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. Oligonucleotide-drug conjugates and their preparation are described in U.S. patent application Ser. No. 09/334,130 (filed Jun. 15, 1999) which is incorporated herein by reference in its entirety.  
       [0055] Representative United States patents that teach the preparation of such oligonucleotide conjugates include, but are not limited to, U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference.  
       [0056] It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide. The present invention also includes antisense compounds which are chimeric compounds. “Chimeric” antisense compounds or “chimeras,” in the context of this invention, are antisense compounds, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, increased stability and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNAse H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide inhibition of gene expression. The cleavage of RNA:RNA hybrids can, in like fashion, be accomplished through the actions of endoribonucleases, such as interferon-induced RNAseL which cleaves both cellular and viral RNA. Consequently, comparable results can often be obtained with shorter oligonucleotides when chimeric oligonucleotides are used, compared to phosphorothioate deoxyoligonucleotides hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art.  
       [0057] Chimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers. Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Pat. Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.  
       [0058] The antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives.  
       [0059] The compounds of the invention may also be admixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, receptor-targeted molecules, oral, rectal, topical or other formulations, for assisting in uptake, distribution and/or absorption. Representative United States patents that teach the preparation of such uptake, distribution and/or absorption-assisting formulations include, but are not limited to, U.S. Pat. Nos. 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291; 5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330; 4,534,899; 5,013,556; 5,108,921; 5,213,804; 5,227,170; 5,264,221; 5,356,633; 5,395,619; 5,416,016; 5,417,978; 5,462,854; 5,469,854; 5,512,295; 5,527,528; 5,534,259; 5,543,152; 5,556,948; 5,580,575; and 5,595,756, each of which is herein incorporated by reference.  
       [0060] The antisense compounds of the invention encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to prodrugs and pharmaceutically acceptable salts of the compounds of the invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents.  
       [0061] The term “prodrug” indicates a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions. In particular, prodrug versions of the oligonucleotides of the invention are prepared as SATE [(S-acetyl-2-thioethyl) phosphate] derivatives according to the methods disclosed in WO 93/24510 to Gosselin et al., published Dec. 9, 1993 or in WO 94/26764 and U.S. Pat. No. 5,770,713 to Imbach et al.  
       [0062] The term “pharmaceutically acceptable salts” refers to physiologically and pharmaceutically acceptable salts of the compounds of the invention: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.  
       [0063] Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al., “Pharmaceutical Salts,”  J. of Pharma Sci.,  1977, 66, 1-19). The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional manner. The free acid forms differ from their respective salt forms somewhat in certain physical properties such as solubility in polar solvents, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. As used herein, a “pharmaceutical addition salt” includes a pharmaceutically acceptable salt of an acid form of one of the components of the compositions of the invention. These include organic or inorganic acid salts of the amines. Preferred acid salts are the hydrochlorides, acetates, salicylates, nitrates and phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include basic salts of a variety of inorganic and organic acids, such as, for example, with inorganic acids, such as for example hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; with organic carboxylic, sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucaric acid, glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid; and with amino acids, such as the 20 alpha-amino acids involved in the synthesis of proteins in nature, for example glutamic acid or aspartic acid, and also with phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 2- or 3-phosphoglycerate, glucose-6-phosphate, N-cyclohexylsulfamic acid (with the formation of cyclamates), or with other acid organic compounds, such as ascorbic acid. Pharmaceutically acceptable salts of compounds may also be prepared with a pharmaceutically acceptable cation. Suitable pharmaceutically acceptable cations are well known to those skilled in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or hydrogen carbonates are also possible.  
       [0064] For oligonucleotides, preferred examples of pharmaceutically acceptable salts include but are not limited to (a) salts formed with cations such as sodium, potassium, ammonium, magnesium, calcium, polyamines such as spermine and spermidine, etc.; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, and the like; and (d) salts formed from elemental anions such as chlorine, bromine, and iodine.  
       [0065] The antisense compounds of the present invention can be utilized for diagnostics, therapeutics, prophylaxis and as research reagents and kits. For therapeutics, an animal, preferably a human, suspected of having a disease or disorder which can be treated by modulating the expression of PAZ/PIWI domain-containing protein is treated by administering antisense compounds in accordance with this invention. The compounds of the invention can be utilized in pharmaceutical compositions by adding an effective amount of an antisense compound to a suitable pharmaceutically acceptable diluent or carrier. Use of the antisense compounds and methods of the invention may also be useful prophylactically, e.g., to prevent or delay infection, inflammation or tumor formation, for example.  
       [0066] The antisense compounds of the invention are useful for research and diagnostics, because these compounds hybridize to nucleic acids encoding PAZ/PIWI domain-containing protein, enabling sandwich and other assays to easily be constructed to exploit this fact. Hybridization of the antisense oligonucleotides of the invention with a nucleic acid encoding PAZ/PIWI domain-containing protein can be detected by means known in the art. Such means may include conjugation of an enzyme to the oligonucleotide, radiolabelling of the oligonucleotide or any other suitable detection means. Kits using such detection means for detecting the level of PAZ/PIWI domain-containing protein in a sample may also be prepared.  
       [0067] The present invention also includes pharmaceutical compositions and formulations which include the antisense compounds of the invention. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Oligonucleotides with at least one 2′-O-methoxyethyl modification are believed to be particularly useful for oral administration.  
       [0068] Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful. Preferred topical formulations include those in which the oligonucleotides of the invention are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Preferred lipids and liposomes include neutral (e.g. dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearolyphosphatidyl choline) negative (e.g. dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g. dioleoyltetramethylaminopropyl DOTAP and dioleoylphosphatidyl ethanolamine DOTMA). Oligonucleotides of the invention may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, oligonucleotides may be complexed to lipids, in particular to cationic lipids. Preferred fatty acids and esters include but are not limited arachidonic acid, oleic acid, eicosanoic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a C 1-10  alkyl ester (e.g. isopropylmyristate IPM), monoglyceride, diglyceride or pharmaceutically acceptable salt thereof. Topical formulations are described in detail in U.S. patent application Ser. No. 09/315,298 filed on May 20, 1999 which is incorporated herein by reference in its entirety.  
       [0069] Compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable. Preferred oral formulations are those in which oligonucleotides of the invention are administered in conjunction with one or more penetration enhancers surfactants and chelators. Preferred surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Preferred bile acids/salts include chenodeoxycholic acid (CDCA) and ursodeoxychenodeoxycholic acid (UDCA), cholic acid, dehydrocholic acid, deoxycholic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, sodium tauro-24,25-dihydro-fusidate and sodium glycodihydrofusidate. Preferred fatty acids include arachidonic acid, undecanoic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1-dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a monoglyceride, a diglyceride or a pharmaceutically acceptable salt thereof (e.g. sodium). Also preferred are combinations of penetration enhancers, for example, fatty acids/salts in combination with bile acids/salts. A particularly preferred combination is the sodium salt of lauric acid, capric acid and UDCA. Further penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. Oligonucleotides of the invention may be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. Oligonucleotide complexing agents include poly-amino acids; polyimines; polyacrylates; polyalkylacrylates, polyoxethanes, polyalkylcyanoacrylates; cationized gelatins, albumins, starches, acrylates, polyethyleneglycols (PEG) and starches; polyalkylcyanoacrylates; DEAE-derivatized polyimines, pollulans, celluloses and starches. Particularly preferred complexing agents include chitosan, N-trimethylchitosan, poly-L-lysine, polyhistidine, polyornithine, polyspermines, protamine, polyvinylpyridine, polythiodiethylaminomethylethylene P(TDAE), polyaminostyrene (e.g. p-amino), poly(methylcyanoacrylate), poly(ethylcyanoacrylate), poly(butylcyanoacrylate), poly(isobutylcyanoacrylate), poly(isohexylcynaoacrylate), DEAE-methacrylate, DEAE-hexylacrylate, DEAE-acrylamide, DEAE-albumin and DEAE-dextran, polymethylacrylate, polyhexylacrylate, poly(D,L-lactic acid), poly(DL-lactic-co-glycolic acid (PLGA), alginate, and polyethyleneglycol (PEG). Oral formulations for oligonucleotides and their preparation are described in detail in U.S. application Ser. No. 08/886,829 (filed Jul. 1, 1997), Ser. No. 09/108,673 (filed Jul. 1, 1998), Ser. No. 09/256,515 (filed Feb. 23, 1999), Ser. No. 09/082,624 (filed May 21, 1998) and Ser. No. 09/315,298 (filed May 20, 1999), each of which is incorporated herein by reference in their entirety.  
       [0070] Compositions and formulations for parenteral, intrathecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.  
       [0071] Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions may be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids.  
       [0072] The pharmaceutical formulations of the present invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.  
       [0073] The compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.  
       [0074] In one embodiment of the present invention the pharmaceutical compositions may be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions, creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product. The preparation of such compositions and formulations is generally known to those skilled in the pharmaceutical and formulation arts and may be applied to the formulation of the compositions of the present invention.  
       [0075] Emulsions  
       [0076] The compositions of the present invention may be prepared and formulated as emulsions. Emulsions are typically heterogenous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 μm in diameter (Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199; Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., Volume 1, p. 245; Block in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 2, p. 335; Higuchi et al., in  Remington&#39;s Pharmaceutical Sciences,  Mack Publishing Co., Easton, Pa., 1985, p. 301). Emulsions are often biphasic systems comprising two immiscible liquid phases intimately mixed and dispersed with each other. In general, emulsions may be of either the water-in-oil (w/o) or the oil-in-water (o/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase, the resulting composition is called a water-in-oil (w/o) emulsion. Alternatively, when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase, the resulting composition is called an oil-in-water (o/w) emulsion. Emulsions may contain additional components in addition to the dispersed phases, and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants may also be present in emulsions as needed. Pharmaceutical emulsions may also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil-in-water-in-oil (o/w/o) and water-in-oil-in-water (w/o/w) emulsions. Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous phase provides an o/w/o emulsion.  
       [0077] Emulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion may be a semisolid or a solid, as is the case of emulsion-style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that may be incorporated into either phase of the emulsion. Emulsifiers may broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199).  
       [0078] Synthetic surfactants, also known as surface active agents, have found wide applicability in the formulation of emulsions and have been reviewed in the literature (Rieger, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285; Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), Marcel Dekker, Inc., New York, N.Y., 1988, volume 1, p. 199). Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants may be classified into different classes based on the nature of the hydrophilic group: nonionic, anionic, cationic and amphoteric (Rieger, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 285).  
       [0079] Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearate.  
       [0080] A large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335; Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199).  
       [0081] Hydrophilic colloids or hydrocolloids include naturally occurring gums and synthetic polymers such as polysaccharides (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth), cellulose derivatives (for example, carboxymethylcellulose and carboxypropylcellulose), and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers). These disperse or swell in water to form colloidal solutions that stabilize emulsions by forming strong interfacial films around the dispersed-phase droplets and by increasing the viscosity of the external phase.  
       [0082] Since emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that may readily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in emulsion formulations include methyl paraben, propyl paraben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, and boric acid. Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. Antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin.  
       [0083] The application of emulsion formulations via dermatological, oral and parenteral routes and methods for their manufacture have been reviewed in the literature (Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of ease of formulation, as well as efficacy from an absorption and bioavailability standpoint (Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Idson, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 199). Mineral-oil base laxatives, oil-soluble vitamins and high fat nutritive-preparations are among the materials that have commonly been administered orally as o/w emulsions.  
       [0084] In one embodiment of the present invention, the compositions of oligonucleotides and nucleic acids are formulated as microemulsions. A microemulsion may be defined as a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution (Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Typically microemulsions are systems that are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a fourth component, generally an intermediate chain-length alcohol to form a transparent system. Therefore, microemulsions have also been described as thermodynamically stable, isotropically clear dispersions of two immiscible liquids that are stabilized by interfacial films of surface-active molecules (Leung and Shah, in:  Controlled Release of Drugs: Polymers and Aggregate Systems,  Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215). Microemulsions commonly are prepared via a combination of three to five components that include oil, water, surfactant, cosurfactant and electrolyte. Whether the microemulsion is of the water-in-oil (w/o) or an oil-in-water (o/w) type is dependent on the properties of the oil and surfactant used and on the structure and geometric packing of the polar heads and hydrocarbon tails of the surfactant molecules (Schott, in  Remington&#39;s Pharmaceutical Sciences,  Mack Publishing Co., Easton, Pa., 1985, p. 271).  
       [0085] The phenomenological approach utilizing phase diagrams has been extensively studied and has yielded a comprehensive knowledge, to one skilled in the art, of how to formulate microemulsions (Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245; Block, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 335). Compared to conventional emulsions, microemulsions offer the advantage of solubilizing water-insoluble drugs in a formulation of thermodynamically stable droplets that are formed spontaneously.  
       [0086] Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non-ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310), tetraglycerol monooleate (MO310), hexaglycerol monooleate (PO310), hexaglycerol pentaoleate (PO500), decaglycerol monocaprate (MCA750), decaglycerol monooleate (MO750), decaglycerol sequioleate (SO750), decaglycerol decaoleate (DAO750), alone or in combination with cosurfactants. The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules. Microemulsions may, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase may typically be, but is not limited to, water, an aqueous solution of the drug, glycerol, PEG300, PEG400, polyglycerols, propylene glycols, and derivatives of ethylene glycol. The oil phase may include, but is not limited to, materials such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, medium chain (C8-C12) mono, di, and triglycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglycolized glycerides, saturated polyglycolized C8-C10 glycerides, vegetable oils and silicone oil.  
       [0087] Microemulsions are particularly of interest from the standpoint of drug solubilization and the enhanced absorption of drugs. Lipid based microemulsions (both o/w and w/o) have been proposed to enhance the oral bioavailability of drugs, including peptides (Constantinides et al.,  Pharmaceutical Research,  1994, 11, 1385-1390; Ritschel,  Meth. Find. Exp. Clin. Pharmacol.,  1993, 13, 205). Microemulsions afford advantages of improved drug solubilization, protection of drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactant-induced alterations in membrane fluidity and permeability, ease of preparation, ease of oral administration over solid dosage forms, improved clinical potency, and decreased toxicity (Constantinides et al.,  Pharmaceutical Research,  1994, 11, 1385; Ho et al.,  J. Pharm. Sci.,  1996, 85, 138-143). Often microemulsions may form spontaneously when their components are brought together at ambient temperature. This may be particularly advantageous when formulating thermolabile drugs, peptides or oligonucleotides. Microemulsions have also been effective in the transdermal delivery of active components in both cosmetic and pharmaceutical applications. It is expected that the microemulsion compositions and formulations of the present invention will facilitate the increased systemic absorption of oligonucleotides and nucleic acids from the gastrointestinal tract, as well as improve the local cellular uptake of oligonucleotides and nucleic acids within the gastrointestinal tract, vagina, buccal cavity and other areas of administration.  
       [0088] Microemulsions of the present invention may also contain additional components and additives such as sorbitan monostearate (Grill 3), Labrasol, and penetration enhancers to improve the properties of the formulation and to enhance the absorption of the oligonucleotides and nucleic acids of the present invention. Penetration enhancers used in the microemulsions of the present invention may be classified as belonging to one of five broad categories—surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p. 92). Each of these classes has been discussed above.  
       [0089] Liposomes  
       [0090] There are many organized surfactant structures besides microemulsions that have been studied and used for the formulation of drugs. These include monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, have attracted great interest because of their specificity and the duration of action they offer from the standpoint of drug delivery. As used in the present invention, the term “liposome” means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers.  
       [0091] Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the composition to be delivered. Cationic liposomes possess the advantage of being able to fuse to the cell wall. Non-cationic liposomes, although not able to fuse as efficiently with the cell wall, are taken up by macrophages in vivo.  
       [0092] In order to cross intact mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdermal gradient. Therefore, it is desirable to use a liposome which is highly deformable and able to pass through such fine pores.  
       [0093] Further advantages of liposomes include; liposomes obtained from natural phospholipids are biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid soluble drugs; liposomes can protect encapsulated drugs in their internal compartments from metabolism and degradation (Rosoff, in  Pharmaceutical Dosage Forms,  Lieberman, Rieger and Banker (Eds.), 1988, Marcel Dekker, Inc., New York, N.Y., volume 1, p. 245). Important considerations in the preparation of liposome formulations are the lipid surface charge, vesicle size and the aqueous volume of the liposomes.  
       [0094] Liposomes are useful for the transfer and delivery of active ingredients to the site of action. Because the liposomal membrane is structurally similar to biological membranes, when liposomes are applied to a tissue, the liposomes start to merge with the cellular membranes and as the merging of the liposome and cell progresses, the liposomal contents are emptied into the cell where the active agent may act.  
       [0095] Liposomal formulations have been the focus of extensive investigation as the mode of delivery for many drugs. There is growing evidence that for topical administration, liposomes present several advantages over other formulations. Such advantages include reduced side-effects related to high systemic absorption of the administered drug, increased accumulation of the administered drug at the desired target, and the ability to administer a wide variety of drugs, both hydrophilic and hydrophobic, into the skin.  
       [0096] Several reports have detailed the ability of liposomes to deliver agents including high-molecular weight DNA into the skin. Compounds including analgesics, antibodies, hormones and high-molecular weight DNAs have been administered to the skin. The majority of applications resulted in the targeting of the upper epidermis.  
       [0097] Liposomes fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged DNA molecules to form a stable complex. The positively charged DNA/liposome complex binds to the negatively charged cell surface and is internalized in an endosome. Due to the acidic pH within the endosome, the liposomes are ruptured, releasing their contents into the cell cytoplasm (Wang et al.,  Biochem. Biophys. Res. Commun.,  1987, 147, 980-985).  
       [0098] Liposomes which are pH-sensitive or negatively-charged, entrap DNA rather than complex with it. Since both the DNA and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some DNA is entrapped within the aqueous interior of these liposomes. pH-sensitive liposomes have been used to deliver DNA encoding the thymidine kinase gene to cell monolayers in culture. Expression of the exogenous gene was detected in the target cells (Zhou et al.,  Journal of Controlled Release,  1992, 19, 269-274).  
       [0099] One major type of liposomal composition includes phospholipids other than naturally-derived phosphatidylcholine. Neutral liposome compositions, for example, can be formed from dimyristoyl phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC). Anionic liposome compositions generally are formed from dimyristoyl phosphatidylglycerol, while anionic fusogenic liposomes are formed primarily from dioleoyl phosphatidylethanolamine (DOPE). Another type of liposomal composition is formed from phosphatidylcholine (PC) such as, for example, soybean PC, and egg PC. Another type is formed from mixtures of phospholipid and/or phosphatidylcholine and/or cholesterol.  
       [0100] Several studies have assessed the topical delivery of liposomal drug formulations to the skin. Application of liposomes containing interferon to guinea pig skin resulted in a reduction of skin herpes sores while delivery of interferon via other means (e.g. as a solution or as an emulsion) were ineffective (Weiner et al.,  Journal of Drug Targeting,  1992, 2, 405-410). Further, an additional study tested the efficacy of interferon administered as part of a liposomal formulation to the administration of interferon using an aqueous system, and concluded that the liposomal formulation was superior to aqueous administration (du Plessis et al.,  Antiviral Research,  1992, 18, 259-265).  
       [0101] Non-ionic liposomal systems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systems comprising non-ionic surfactant and cholesterol. Non-ionic liposomal formulations comprising Novasome™ I (glyceryl dilaurate/cholesterol/polyoxyethylene-10-stearyl ether) and Novasome™ II (glyceryl distearate/cholesterol/polyoxyethylene-10-stearyl ether) were used to deliver cyclosporin-A into the dermis of mouse skin. Results indicated that such non-ionic liposomal systems were effective in facilitating the deposition of cyclosporin-A into different layers of the skin (Hu et al.  S.T.P. Pharma. Sci.,  1994, 4, 6, 466).  
       [0102] Liposomes also include “sterically stabilized” liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome (A) comprises one or more glycolipids, such as monosialoganglioside G M1 , or (B) is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. While not wishing to be bound by any particular theory, it is thought in the art that, at least for sterically stabilized liposomes containing gangliosides, sphingomyelin, or PEG-derivatized lipids, the enhanced circulation half-life of these sterically stabilized liposomes derives from a reduced uptake into cells of the reticuloendothelial system (RES) (Allen et al.,  FEBS Letters,  1987, 223, 42; Wu et al.,  Cancer Research,  1993, 53, 3765).  
       [0103] Various liposomes comprising one or more glycolipids are known in the art. Papahadjopoulos et al. ( Ann. N.Y. Acad. Sci.,  1987, 507, 64) reported the ability of monosialoganglioside G M1 , galactocerebroside sulfate and phosphatidylinositol to improve blood half-lives of liposomes. These findings were expounded upon by Gabizon et al. ( Proc. Natl. Acad. Sci. U.S.A.,  1988, 85, 6949). U.S. Pat. No. 4,837,028 and WO 88/04924, both to Allen et al., disclose liposomes comprising (1) sphingomyelin and (2) the ganglioside G M1  or a galactocerebroside sulfate ester. U.S. Pat. No. 5,543,152 (Webb et al.) discloses liposomes comprising sphingomyelin. Liposomes comprising 1,2-sn-dimyristoylphosphatidylcholine are disclosed in WO 97/13499 (Lim et al.).  
       [0104] Many liposomes comprising lipids derivatized with one or more hydrophilic polymers, and methods of preparation thereof, are known in the art. Sunamoto et al. ( Bull. Chem. Soc. Jpn.,  1980, 53, 2778) described liposomes comprising a nonionic detergent, 2C 12 15G, that contains a PEG moiety. Illum et al. ( FEBS Lett.,  1984, 167, 79) noted that hydrophilic coating of polystyrene particles with polymeric glycols results in significantly enhanced blood half-lives. Synthetic phospholipids modified by the attachment of carboxylic groups of polyalkylene glycols (e.g., PEG) are described by Sears (U.S. Pat. Nos. 4,426,330 and 4,534,899). Klibanov et al. ( FEBS Lett.,  1990, 268, 235) described experiments demonstrating that liposomes comprising phosphatidylethanolamine (PE) derivatized with PEG or PEG stearate have significant increases in blood circulation half-lives. Blume et al. ( Biochimica et Biophysica Acta,  1990, 1029, 91) extended such observations to other PEG-derivatized phospholipids, e.g., DSPE-PEG, formed from the combination of distearoylphosphatidylethanolamine (DSPE) and PEG. Liposomes having covalently bound PEG moieties on their external surface are described in European Patent No. EP 0 445 131 B1 and WO 90/04384 to Fisher. Liposome compositions containing 1-20 mole percent of PE derivatized with PEG, and methods of use thereof, are described by Woodle et al. (U.S. Pat. Nos. 5,013,556 and 5,356,633) and Martin et al. (U.S. Pat. No. 5,213,804 and European Patent No. EP 0 496 813 B1). Liposomes comprising a number of other lipid-polymer conjugates are disclosed in WO 91/05545 and U.S. Pat. No. 5,225,212 (both to Martin et al.) and in WO 94/20073 (Zalipsky et al.) Liposomes comprising PEG-modified ceramide lipids are described in WO 96/10391 (Choi et al.). U.S. Pat. No. 5,540,935 (Miyazaki et al.) and U.S. Pat. No. 5,556,948 (Tagawa et al.) describe PEG-containing liposomes that can be further derivatized with functional moieties on their surfaces.  
       [0105] A limited number of liposomes comprising nucleic acids are known in the art. WO 96/40062 to Thierry et al. discloses methods for encapsulating high molecular weight nucleic acids in liposomes. U.S. Pat. No. 5,264,221 to Tagawa et al. discloses protein-bonded liposomes and asserts that the contents of such liposomes may include an antisense RNA. U.S. Pat. No. 5,665,710 to Rahman et al. describes certain methods of encapsulating oligodeoxynucleotides in liposomes. WO 97/04787 to Love et al. discloses liposomes comprising antisense oligonucleotides targeted to the raf gene.  
       [0106] Transfersomes are yet another type of liposomes, and are highly deformable lipid aggregates which are attractive candidates for drug delivery vehicles. Transfersomes may be described as lipid droplets which are so highly deformable that they are easily able to penetrate through pores which are smaller than the droplet. Transfersomes are adaptable to the environment in which they are used, e.g. they are self-optimizing (adaptive to the shape of pores in the skin), self-repairing, frequently reach their targets without fragmenting, and often self-loading. To make transfersomes it is possible to add surface edge-activators, usually surfactants, to a standard liposomal composition. Transfersomes have been used to deliver serum albumin to the skin. The transfersome-mediated delivery of serum albumin has been shown to be as effective as subcutaneous injection of a solution containing serum albumin.  
       [0107] Surfactants find wide application in formulations such as emulsions (including microemulsions) and liposomes. The most common way of classifying and ranking the properties of the many different types of surfactants, both natural and synthetic, is by the use of the hydrophile/lipophile balance (HLB). The nature of the hydrophilic group (also known as the “head”) provides the most useful means for categorizing the different surfactants used in formulations (Rieger, in  Pharmaceutical Dosage Forms,  Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).  
       [0108] If the surfactant molecule is not ionized, it is classified as a nonionic surfactant. Nonionic surfactants find wide application in pharmaceutical and cosmetic products and are usable over a wide range of pH values. In general their HLB values range from 2 to about 18 depending on their structure. Nonionic surfactants include nonionic esters such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esters. Nonionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated/propoxylated block polymers are also included in this class. The polyoxyethylene surfactants are the most popular members of the nonionic surfactant class.  
       [0109] If the surfactant molecule carries a negative charge when it is dissolved or dispersed in water, the surfactant is classified as anionic. Anionic surfactants include carboxylates such as soaps, acyl lactylates, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such as alkyl benzene sulfonates, acyl isethionates, acyl taurates and sulfosuccinates, and phosphates. The most important members of the anionic surfactant class are the alkyl sulfates and the soaps.  
       [0110] If the surfactant molecule carries a positive charge when it is dissolved or dispersed in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium salts and ethoxylated amines. The quaternary ammonium salts are the most used members of this class.  
       [0111] If the surfactant molecule has the ability to carry either a positive or negative charge, the surfactant is classified as amphoteric. Amphoteric surfactants include acrylic acid derivatives, substituted alkylamides, N-alkylbetaines and phosphatides.  
       [0112] The use of surfactants in drug products, formulations and in emulsions has been reviewed (Rieger, in  Pharmaceutical Dosage Forms,  Marcel Dekker, Inc., New York, N.Y., 1988, p. 285).  
       [0113] Penetration Enhancers  
       [0114] In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly oligonucleotides, to the skin of animals. Most drugs are present in solution in both ionized and nonionized forms. However, usually only lipid soluble or lipophilic drugs readily cross cell membranes. It has been discovered that even non-lipophilic drugs may cross cell membranes if the membrane to be crossed is treated with a penetration enhancer. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs.  
       [0115] Penetration enhancers may be classified as belonging to one of five broad categories, i.e., surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p.92). Each of the above mentioned classes of penetration enhancers are described below in greater detail.  
       [0116] Surfactants: In connection with the present invention, surfactants (or “surface-active agents”) are chemical entities which, when dissolved in an aqueous solution, reduce the surface tension of the solution or the interfacial tension between the aqueous solution and another liquid, with the result that absorption of oligonucleotides through the mucosa is enhanced. In addition to bile salts and fatty acids, these penetration enhancers include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxyethylene-20-cetyl ether) (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p.92); and perfluorochemical emulsions, such as FC-43. Takahashi et al.,  J. Pharm. Pharmacol.,  1988, 40, 252).  
       [0117] Fatty acids: Various fatty acids and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid (n-decanoic acid), myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein (1-monooleoyl-rac-glycerol), dilaurin, caprylic acid, arachidonic acid, glycerol 1-monocaprate, 1-dodecylazacycloheptan-2-one, acylcarnitines, acylcholines, C 1-10  alkyl esters thereof (e.g., methyl, isopropyl and t-butyl), and mono- and di-glycerides thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, p.92; Muranishi,  Critical Reviews in Therapeutic Drug Carrier Systems,  1990, 7, 1-33; El Hariri et al., J. Pharm. Pharmacol., 1992, 44, 651-654).  
       [0118] Bile salts: The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitamins (Brunton, Chapter 38 in: Goodman &amp; Gilman&#39;s  The Pharmacological Basis of Therapeutics,  9th Ed., Hardman et al. Eds., McGraw-Hill, New York, 1996, pp. 934-935). Various natural bile salts, and their synthetic derivatives, act as penetration enhancers. Thus the term “bile salts” includes any of the naturally occurring components of bile as well as any of their synthetic derivatives. The bile salts of the invention include, for example, cholic acid (or its pharmaceutically acceptable sodium salt, sodium cholate), dehydrocholic acid (sodium dehydrocholate), deoxycholic acid (sodium deoxycholate), glucholic acid (sodium glucholate), glycholic acid (sodium glycocholate), glycodeoxycholic acid (sodium glycodeoxycholate), taurocholic acid (sodium taurocholate), taurodeoxycholic acid (sodium taurodeoxycholate), chenodeoxycholic acid (sodium chenodeoxycholate), ursodeoxycholic acid (UDCA), sodium tauro-24,25-dihydro-fusidate (STDHF), sodium glycodihydrofusidate and polyoxyethylene-9-lauryl ether (POE) (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, page 92; Swinyard, Chapter 39 In:  Remington&#39;s Pharmaceutical Sciences,  18th Ed., Gennaro, ed., Mack Publishing Co., Easton, Pa., 1990, pages 782-783; Muranishi,  Critical Reviews in Therapeutic Drug Carrier Systems,  1990, 7, 1-33; Yamamoto et al.,  J. Pharm. Exp. Ther.,  1992, 263, 25; Yamashita et al.,  J. Pharm. Sci.,  1990, 79, 579-583).  
       [0119] Chelating Agents: Chelating agents, as used in connection with the present invention, can be defined as compounds that remove metallic ions from solution by forming complexes therewith, with the result that absorption of oligonucleotides through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitors, as most characterized DNA nucleases require a divalent metal ion for catalysis and are thus inhibited by chelating agents (Jarrett,  J. Chromatogr.,  1993, 618, 315-339). Chelating agents of the invention include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate), N-acyl derivatives of collagen, laureth-9 and N-amino acyl derivatives of beta-diketones (enamines) (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, page 92; Muranishi,  Critical Reviews in Therapeutic Drug Carrier Systems,  1990, 7, 1-33; Buur et al.,  J. Control Rel.,  1990, 14, 43-51).  
       [0120] Non-chelating non-surfactants: As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate insignificant activity as chelating agents or as surfactants but that nonetheless enhance absorption of oligonucleotides through the alimentary mucosa (Muranishi,  Critical Reviews in Therapeutic Drug Carrier Systems,  1990, 7, 1-33). This class of penetration enhancers include, for example, unsaturated cyclic ureas, 1-alkyl- and 1-alkenylazacyclo-alkanone derivatives (Lee et al.,  Critical Reviews in Therapeutic Drug Carrier Systems,  1991, page 92); and non-steroidal anti-inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al.,  J. Pharm. Pharmacol.,  1987, 39, 621-626).  
       [0121] Agents that enhance uptake of oligonucleotides at the cellular level may also be added to the pharmaceutical and other compositions of the present invention. For example, cationic lipids, such as lipofectin (Junichi et al, U.S. Pat. No. 5,705,188), cationic glycerol derivatives, and polycationic molecules, such as polylysine (Lollo et al., PCT Application WO 97/30731), are also known to enhance the cellular uptake of oligonucleotides.  
       [0122] Other agents may be utilized to enhance the penetration of the administered nucleic acids, including glycols such as ethylene glycol and propylene glycol, pyrrols such as 2-pyrrol, azones, and terpenes such as limonene and menthone.  
       [0123] Carriers  
       [0124] Certain compositions of the present invention also incorporate carrier compounds in the formulation. As used herein, “carrier compound” or “carrier” can refer to a nucleic acid, or analog thereof, which is inert (i.e., does not possess biological activity per se) but is recognized as a nucleic acid by in vivo processes that reduce the bioavailability of a nucleic acid having biological activity by, for example, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a substantial reduction of the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reservoirs, presumably due to competition between the carrier compound and the nucleic acid for a common receptor. For example, the recovery of a partially phosphorothioate oligonucleotide in hepatic tissue can be reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4′isothiocyano-stilbene-2,2′-disulfonic acid (Miyao et al.,  Antisense Res. Dev.,  1995, 5, 115-121; Takakura et al.,  Antisense  &amp;  Nucl. Acid Drug Dev.,  1996, 6, 177-183).  
       [0125] Excipients  
       [0126] In contrast to a carrier compound, a “pharmaceutical carrier” or “excipient” is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient may be liquid or solid and is selected, with the planned manner of administration in mind, so as to provide for the desired bulk, consistency, etc., when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose, etc.); fillers (e.g., lactose and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, stearic acid, metallic stearates, hydrogenated vegetable oils, corn starch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., sodium lauryl sulphate, etc.).  
       [0127] Pharmaceutically acceptable organic or inorganic excipient suitable for non-parenteral administration which do not deleteriously react with nucleic acids can also be used to formulate the compositions of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.  
       [0128] Formulations for topical administration of nucleic acids may include sterile and non-sterile aqueous solutions, non-aqueous solutions in common solvents such as alcohols, or solutions of the nucleic acids in liquid or solid oil bases. The solutions may also contain buffers, diluents and other suitable additives. Pharmaceutically acceptable organic or inorganic excipients suitable for non-parenteral administration which do not deleteriously react with nucleic acids can be used.  
       [0129] Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like.  
       [0130] Other Components  
       [0131] The compositions of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(s) of the formulation.  
       [0132] Aqueous suspensions may contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.  
       [0133] Certain embodiments of the invention provide pharmaceutical compositions containing (a) one or more antisense compounds and (b) one or more other chemotherapeutic agents which function by a non-antisense mechanism. Examples of such chemotherapeutic agents include but are not limited to daunorubicin, daunomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, esorubicin, bleomycin, mafosfamide, ifosfamide, cytosine arabinoside, bis-chloroethylnitrosurea, busulfan, mitomycin C, actinomycin D, mithramycin, prednisone, hydroxyprogesterone, testosterone, tamoxifen, dacarbazine, procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil, methylcyclohexylnitrosurea, nitrogen mustards, melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-azacytidine, hydroxyurea, deoxycoformycin, 4-hydroxyperoxycyclophosphoramide, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5-FUdR), methotrexate (MTX), colchicine, taxol, vincristine, vinblastine, etoposide (VP-16), trimetrexate, irinotecan, topotecan, gemcitabine, teniposide, cisplatin and diethylstilbestrol (DES). See, generally,  The Merck Manual of Diagnosis and Therapy,  15th Ed. 1987, pp. 1206-1228, Berkow et al., eds., Rahway, N.J. When used with the compounds of the invention, such chemotherapeutic agents may be used individually (e.g., 5-FU and oligonucleotide), sequentially (e.g., 5-FU and oligonucleotide for a period of time followed by MTX and oligonucleotide), or in combination with one or more other such chemotherapeutic agents (e.g., 5-FU, MTX and oligonucleotide, or 5-FU, radiotherapy and oligonucleotide). Anti-inflammatory drugs, including but not limited to nonsteroidal anti-inflammatory drugs and corticosteroids, and antiviral drugs, including but not limited to ribivirin, vidarabine, acyclovir and ganciclovir, may also be combined in compositions of the invention. See, generally,  The Merck Manual of Diagnosis and Therapy,  15th Ed., Berkow et al., eds., 1987, Rahway, N.J., pages 2499-2506 and 46-49, respectively). Other non-antisense chemotherapeutic agents are also within the scope of this invention. Two or more combined compounds may be used together or sequentially.  
       [0134] In another related embodiment, compositions of the invention may contain one or more antisense compounds, particularly oligonucleotides, targeted to a first nucleic acid and one or more additional antisense compounds targeted to a second nucleic acid target. Numerous examples of antisense compounds are known in the art. Two or more combined compounds may be used together or sequentially.  
       [0135] The formulation of therapeutic compositions and their subsequent administration is believed to be within the skill of those in the art. Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual oligonucleotides, and can generally be estimated based on EC 50 s found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 ug to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the oligonucleotide is administered in maintenance doses, ranging from 0.01 ug to 100 g per kg of body weight, once or more daily, to once every 20 years.  
       [0136] While the present invention has been described with specificity in accordance with certain of its preferred embodiments, the following examples serve only to illustrate the invention and are not intended to limit the same.  
     
    
    
     EXAMPLES  
     Example 1  
     [0137] Nucleoside Phosphoramidites for Oligonucleotide Synthesis Deoxy and 2′-alkoxy Amidites  
     [0138] 2′-Deoxy and 2′-methoxy beta-cyanoethyldiisopropyl phosphoramidites were purchased from commercial sources (e.g. Chemgenes, Needham Mass. or Glen Research, Inc. Sterling Va.). Other 2′-O-alkoxy substituted nucleoside amidites are prepared as described in U.S. Pat. No. 5,506,351, herein incorporated by reference. For oligonucleotides synthesized using 2′-alkoxy amidites, optimized synthesis cycles were developed that incorporate multiple steps coupling longer wait times relative to standard synthesis cycles.  
     [0139] The following abbreviations are used in the text: thin layer chromatography (TLC), melting point (MP), high pressure liquid chromatography (HPLC), Nuclear Magnetic Resonance (NMR), argon (Ar), methanol (MeOH), dichloromethane (CH 2 Cl 2 ), triethylamine (TEA), dimethyl formamide (DMF), ethyl acetate (EtOAc), dimethyl sulfoxide (DMSO), tetrahydrofuran (THF).  
     [0140] Oligonucleotides containing 5-methyl-2′-deoxycytidine (5-Me-dC) nucleotides were synthesized according to published methods (Sanghvi, et. al.,  Nucleic Acids Research,  1993, 21, 3197-3203) using commercially available phosphoramidites (Glen Research, Sterling Va. or ChemGenes, Needham Mass.) or prepared as follows:  
     [0141] Preparation of 5′-O-Dimethoxytrityl-thymidine Intermediate for 5-methyl dC Amidite  
     [0142] To a 50 L glass reactor equipped with air stirrer and Ar gas line was added thymidine (1.00 kg, 4.13 mol) in anhydrous pyridine (6 μL) at ambient temperature. Dimethoxytrityl (DMT) chloride (1.47 kg, 4.34 mol, 1.05 eq) was added as a solid in four portions over 1 h. After 30 min, TLC indicated approx. 95% product, 2% thymidine, 5% DMT reagent and by-products and 2% 3′,5′-bis DMT product (R f  in EtOAc 0.45, 0.05, 0.98, 0.95 respectively). Saturated sodium bicarbonate (4 L) and CH 2 Cl 2  were added with stirring (pH of the aqueous layer 7.5). An additional 18 L of water was added, the mixture was stirred, the phases were separated, and the organic layer was transferred to a second 50 L vessel. The aqueous layer was extracted with additional CH 2 Cl 2  (2×2 L). The combined organic layer was washed with water (10 L) and then concentrated in a rotary evaporator to approx. 3.6 kg total weight. This was redissolved in CH 2 Cl 2  (3.5 L), added to the reactor followed by water (6 L) and hexanes (13 L). The mixture was vigorously stirred and seeded to give a fine white suspended solid starting at the interface. After stirring for 1 h, the suspension was removed by suction through a ½″ diameter teflon tube into a 20 L suction flask, poured onto a 25 cm Coors Buchner funnel, washed with water (2×3 L) and a mixture of hexanes-CH 2 Cl 2  (4:1, 2×3 L) and allowed to air dry overnight in pans (1″ deep). This was further dried in a vacuum oven (75° C., 0.1 mm Hg, 48 h) to a constant weight of 2072 g (93%) of a white solid, (mp 122-124° C.). TLC indicated a trace contamination of the bis DMT product. NMR spectroscopy also indicated that 1-2 mole percent pyridine and about 5 mole percent of hexanes was still present.  
     [0143] Preparation of 5′-O-Dimethoxytrityl-2′-deoxy-5-methylcytidine Intermediate for 5-methyl-dC Amidite  
     [0144] To a 50 L Schott glass-lined steel reactor equipped with an electric stirrer, reagent addition pump (connected to an addition funnel), heating/cooling system, internal thermometer and an Ar gas line was added 5′-O-dimethoxytrityl-thymidine (3.00 kg, 5.51 mol), anhydrous acetonitrile (25 L) and TEA (12.3 L, 88.4 mol, 16 eq). The mixture was chilled with stirring to −10° C. internal temperature (external −20° C.). Trimethylsilylchloride (2.1 L, 16.5 mol, 3.0 eq) was added over 30 minutes while maintaining the internal temperature below −5° C., followed by a wash of anhydrous acetonitrile (1 L). Note: the reaction is mildly exothermic and copious hydrochloric acid fumes form over the course of the addition. The reaction was allowed to warm to 0° C. and the reaction progress was confirmed by TLC (EtOAc-hexanes 4:1; R f  0.43 to 0.84 of starting material and silyl product, respectively). Upon completion, triazole (3.05 kg, 44 mol, 8.0 eq) was added the reaction was cooled to −20° C. internal temperature (external −30° C.). Phosphorous oxychloride (1035 mL, 11.1 mol, 2.01 eq) was added over 60 min so as to maintain the temperature between −20° C. and −10° C. during the strongly exothermic process, followed by a wash of anhydrous acetonitrile (1 L). The reaction was warmed to 0° C. and stirred for 1 h. TLC indicated a complete conversion to the triazole product (R f  0.83 to 0.34 with the product spot glowing in long wavelength UV light). The reaction mixture was a peach-colored thick suspension, which turned darker red upon warming without apparent decomposition. The reaction was cooled to −15° C. internal temperature and water (5 L) was slowly added at a rate to maintain the temperature below +10° C. in order to quench the reaction and to form a homogenous solution. (Caution: this reaction is initially very strongly exothermic). Approximately one-half of the reaction volume (22 L) was transferred by air pump to another vessel, diluted with EtOAc (12 L) and extracted with water (2×8 L). The combined water layers were back-extracted with EtOAc (6 L). The water layer was discarded and the organic layers were concentrated in a 20 L rotary evaporator to an oily foam. The foam was coevaporated with anhydrous acetonitrile (4 L) to remove EtOAc. (note: dioxane may be used instead of anhydrous acetonitrile if dried to a hard foam). The second half of the reaction was treated in the same way. Each residue was dissolved in dioxane (3 L) and concentrated ammonium hydroxide (750 mL) was added. A homogenous solution formed in a few minutes and the reaction was allowed to stand overnight (although the reaction is complete within 1 h).  
     [0145] TLC indicated a complete reaction (product R f  0.35 in EtOAc-MeOH 4:1). The reaction solution was concentrated on a rotary evaporator to a dense foam. Each foam was slowly redissolved in warm EtOAc (4 L; 50° C.), combined in a 50 L glass reactor vessel, and extracted with water (2×4L) to remove the triazole by-product. The water was back-extracted with EtOAc (2 L). The organic layers were combined and concentrated to about 8 kg total weight, cooled to 0° C. and seeded with crystalline product. After 24 hours, the first crop was collected on a 25 cm Coors Buchner funnel and washed repeatedly with EtOAc (3×3L) until a white powder was left and then washed with ethyl ether (2×3L). The solid was put in pans (1″ deep) and allowed to air dry overnight. The filtrate was concentrated to an oil, then redissolved in EtOAc (2 L), cooled and seeded as before. The second crop was collected and washed as before (with proportional solvents) and the filtrate was first extracted with water (2×1L) and then concentrated to an oil. The residue was dissolved in EtOAc (1 L) and yielded a third crop which was treated as above except that more washing was required to remove a yellow oily layer.  
     [0146] After air-drying, the three crops were dried in a vacuum oven (50° C., 0.1 mm Hg, 24 h) to a constant weight (1750, 600 and 200 g, respectively) and combined to afford 2550 g (85%) of a white crystalline product (MP 215-217° C.) when TLC and NMR spectroscopy indicated purity. The mother liquor still contained mostly product (as determined by TLC) and a small amount of triazole (as determined by NMR spectroscopy), bis DMT product and unidentified minor impurities. If desired, the mother liquor can be purified by silica gel chromatography using a gradient of MeOH (0-25%) in EtOAc to further increase the yield.  
     [0147] Preparation of 5′-O-Dimethoxytrityl-2′-deoxy-N-4-benzoyl-5-methylcytidine Penultimate Intermediate for 5-methyl dC Amidite  
     [0148] Crystalline 5′-O-dimethoxytrityl-5-methyl-2′-deoxycytidine (2000 g, 3.68 mol) was dissolved in anhydrous DMF (6.0 kg) at ambient temperature in a 50 L glass reactor vessel equipped with an air stirrer and argon line. Benzoic anhydride (Chem Impex not Aldrich, 874 g, 3.86 mol, 1.05 eq) was added and the reaction was stirred at ambient temperature for 8 h. TLC (CH 2 Cl 2 -EtOAc; CH 2 Cl 2 -EtOAc 4:1; R f  0.25) indicated approx. 92% complete reaction. An additional amount of benzoic anhydride (44 g, 0.19 mol) was added. After a total of 18 h, TLC indicated approx. 96% reaction completion. The solution was diluted with EtOAc (20 L), TEA (1020 mL, 7.36 mol, ca 2.0 eq) was added with stirring, and the mixture was extracted with water (15 L, then 2×10 L). The aqueous layer was removed (no back-extraction was needed) and the organic layer was concentrated in 2×20 L rotary evaporator flasks until a foam began to form. The residues were coevaporated with acetonitrile (1.5 L each) and dried (0.1 mm Hg, 25° C., 24 h) to 2520 g of a dense foam. High pressure liquid chromatography (HPLC) revealed a contamination of 6.3% of N4, 3′-O-dibenzoyl product, but very little other impurities.  
     [0149] THe product was purified by Biotage column chromatography (5 kg Biotage) prepared with 65:35:1 hexanes-EtOAc-TEA (4L). The crude product (800 g),dissolved in CH 2 Cl 2  (2 L), was applied to the column. The column was washed with the 65:35:1 solvent mixture (20 kg), then 20:80:1 solvent mixture (10 kg), then 99:1 EtOAc:TEA (17 kg). The fractions containing the product were collected, and any fractions containing the product and impurities were retained to be resubjected to column chromatography. The column was reequilibrated with the original 65:35:1 solvent mixture (17 kg). A second batch of crude product (840 g) was applied to the column as before. The column was washed with the following solvent gradients: 65:35:1 (9 kg), 55:45:1 (20 kg), 20:80:1 (10 kg), and 99:1 EtOAc:TEA (15 kg). The column was reequilibrated as above, and a third batch of the crude product (850 g) plus impure fractions recycled from the two previous columns (28 g) was purified following the procedure for the second batch. The fractions containing pure product combined and concentrated on a 20L rotary evaporator, coevaporated with acetontirile (3 L) and dried (0.1 mm Hg, 48 h, 25° C.) to a constant weight of 2023 g (85%) of white foam and 20 g of slightly contaminated product from the third run. HPLC indicated a purity of 99.8% with the balance as the diBenzoyl product.  
     [0150] [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N 4 -benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (5-methyl dC Amidite)  
     [0151] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N 4 -benzoyl-5-methylcytidine (998 g, 1.5 mol) was dissolved in anhydrous DMF (2 L). The solution was co-evaporated with toluene (300 ml) at 50° C. under reduced pressure, then cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (680 g, 2.26 mol) and tetrazole (52.5 g, 0.75 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (15 ml) was added and the mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (2.5 L) and water (600 ml), and extracted with hexane (3×3 L). The mixture was diluted with water (1.2 L) and extracted with a mixture of toluene (7.5 L) and hexane (6 L). The two layers were separated, the upper layer was washed with DMF-water (7:3 v/v, 3×2 L) and water (3×2 L), and the phases were separated. The organic layer was dried (Na 2 SO 4 ), filtered and rotary evaporated. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried to a constant weight (25° C., 0.1 mm Hg, 40 h) to afford 1250 μg an off-white foam solid (96%).  
     [0152] 2′-Fluoro Amidites  
     [0153] 2′-Fluorodeoxyadenosine Amidites  
     [0154] 2′-fluoro oligonucleotides were synthesized as described previously [Kawasaki, et. al.,  J. Med. Chem.,  1993, 36, 831-841] and U.S. Pat. No. 5,670,633, herein incorporated by reference. The preparation of 2′-fluoropyrimidines containing a 5-methyl substitution are described in U.S. Pat. No. 5,861,493. Briefly, the protected nucleoside N6-benzoyl-2′-deoxy-2′-fluoroadenosine was synthesized utilizing commercially available 9-beta-D-arabinofuranosyladenine as starting material and whereby the 2′-alpha-fluoro atom is introduced by a S N 2-displacement of a 2′-beta-triflate group. Thus N6-benzoyl-9-beta-D-arabinofuranosyladenine was selectively protected in moderate yield as the 3′,5′-ditetrahydropyranyl (THP) intermediate. Deprotection of the THP and N6-benzoyl groups was accomplished using standard methodologies to obtain the 5′-dimethoxytrityl-(DMT) and 5′-DMT-3′-phosphoramidite intermediates.  
     [0155] 2′-Fluorodeoxyguanosine  
     [0156] The synthesis of 2′-deoxy-2′-fluoroguanosine was accomplished using tetraisopropyldisiloxanyl (TPDS) protected 9-beta-D-arabinofuranosylguanine as starting material, and conversion to the intermediate isobutyryl-arabinofuranosylguanosine. Alternatively, isobutyryl-arabinofuranosylguanosine was prepared as described by Ross et al., ( Nucleosides  &amp;  Nucleosides,  16, 1645, 1997). Deprotection of the TPDS group was followed by protection of the hydroxyl group with THP to give isobutyryl di-THP protected arabinofuranosylguanine. Selective O-deacylation and triflation was followed by treatment of the crude product with fluoride, then deprotection of the THP groups. Standard methodologies were used to obtain the 5′-DMT- and 5′-DMT-3′-phosphoramidites.  
     [0157] 2′-Fluorouridine  
     [0158] Synthesis of 2′-deoxy-2′-fluorouridine was accomplished by the modification of a literature procedure in which 2,2′-anhydro-1-beta-D-arabinofuranosyluracil was treated with 70% hydrogen fluoride-pyridine. Standard procedures were used to obtain the 5′-DMT and 5′-DMT-3′phosphoramidites.  
     [0159] 2′-Fluorodeoxycytidine  
     [0160] 2′-deoxy-2′-fluorocytidine was synthesized via amination of 2′-deoxy-2′-fluorouridine, followed by selective protection to give N4-benzoyl-2′-deoxy-2′-fluorocytidine. Standard procedures were used to obtain the 5′-DMT and 5′-DMT-3′phosphoramidites.  
     [0161] 2′-O-(2-Methoxyethyl) Modified Amidites  
     [0162] 2′-O-Methoxyethyl-substituted nucleoside amidites (otherwise known as MOE amidites) are prepared as follows, or alternatively, as per the methods of Martin, P., (Helvetica Chimica Acta, 1995, 78, 486-504).  
     [0163] Preparation of 2′-O-(2-methoxyethyl)-5-methyluridine Intermediate  
     [0164] 2,2′-Anhydro-5-methyl-uridine (2000 g, 8.32 mol), tris(2-methoxyethyl)borate (2504 g, 10.60 mol), sodium bicarbonate (60 g, 0.70 mol) and anhydrous 2-methoxyethanol (5 L) were combined in a 12 L three necked flask and heated to 130° C. (internal temp) at atmospheric pressure, under an argon atmosphere with stirring for 21 h. TLC indicated a complete reaction. The solvent was removed under reduced pressure until a sticky gum formed (50-85° C. bath temp and 100-11 mm Hg) and the residue was redissolved in water (3 L) and heated to boiling for 30 min in order the hydrolyze the borate esters. The water was removed under reduced pressure until a foam began to form and then the process was repeated. HPLC indicated about 77% product, 15% dimer (5′ of product attached to 2′ of starting material) and unknown derivatives, and the balance was a single unresolved early eluting peak.  
     [0165] The gum was redissolved in brine (3 L), and the flask was rinsed with additional brine (3 L). The combined aqueous solutions were extracted with chloroform (20 L) in a heavier-than continuous extractor for 70 h. The chloroform layer was concentrated by rotary evaporation in a 20 L flask to a sticky foam (2400 g). This was coevaporated with MeOH (400 mL) and EtOAc (8 L) at 75° C. and 0.65 atm until the foam dissolved at which point the vacuum was lowered to about 0.5 atm. After 2.5 L of distillate was collected a precipitate began to form and the flask was removed from the rotary evaporator and stirred until the suspension reached ambient temperature. EtOAc (2 L) was added and the slurry was filtered on a 25 cm table top Buchner funnel and the product was washed with EtOAc (3×2 L). The bright white solid was air dried in pans for 24 h then further dried in a vacuum oven (50° C., 0.1 mm Hg, 24 h) to afford 1649 g of a white crystalline solid (mp 115.5-116.5° C.).  
     [0166] The brine layer in the 20 L continuous extractor was further extracted for 72 h with recycled chloroform. The chloroform was concentrated to 120 g of oil and this was combined with the mother liquor from the above filtration (225 g), dissolved in brine (250 mL) and extracted once with chloroform (250 mL). The brine solution was continuously extracted and the product was crystallized as described above to afford an additional 178 g of crystalline product containing about 2% of thymine. The combined yield was 1827 g (69.4%). HPLC indicated about 99.5% purity with the balance being the dimer.  
     [0167] Preparation of 5′-O-DMT-2′-O-(2-methoxyethyl)-5-methyluridine Penultimate Intermediate  
     [0168] In a 50 L glass-lined steel reactor, 2′-O-(2-methoxyethyl)-5-methyl-uridine (MOE-T, 1500 g, 4.738 mol), lutidine (1015 g, 9.476 mol) were dissolved in anhydrous acetonitrile (15 L). The solution was stirred rapidly and chilled to −10° C. (internal temperature). Dimethoxytriphenylmethyl chloride (1765.7 g, 5.21 mol) was added as a solid in one portion. The reaction was allowed to warm to −2° C. over 1 h. (Note: The reaction was monitored closely by TLC (EtOAc) to determine when to stop the reaction so as to not generate the undesired bis-DMT substituted side product). The reaction was allowed to warm from −2 to 3° C. over 25 min. then quenched by adding MeOH (300 mL) followed after 10 min by toluene (16 L) and water (16 L). The solution was transferred to a clear 50 L vessel with a bottom outlet, vigorously stirred for 1 minute, and the layers separated. The aqueous layer was removed and the organic layer was washed successively with 10% aqueous citric acid (8 L) and water (12 L). The product was then extracted into the aqueous phase by washing the toluene solution with aqueous sodium hydroxide (0.5N, 16 L and 8 L). The combined aqueous layer was overlayed with toluene (12 L) and solid citric acid (8 moles, 1270 g) was added with vigorous stirring to lower the pH of the aqueous layer to 5.5 and extract the product into the toluene. The organic layer was washed with water (10 L) and TLC of the organic layer indicated a trace of DMT-O-Me, bis DMT and dimer DMT.  
     [0169] The toluene solution was applied to a silica gel column (6 L sintered glass funnel containing approx. 2 kg of silica gel slurried with toluene (2 L) and TEA (25 mL)) and the fractions were eluted with toluene (12 L) and EtOAc (3×4 L) using vacuum applied to a filter flask placed below the column. The first EtOAc fraction containing both the desired product and impurities were resubjected to column chromatography as above. The clean fractions were combined, rotary evaporated to a foam, coevaporated with acetonitrile (6 L) and dried in a vacuum oven (0.1 mm Hg, 40 h, 40° C.) to afford 2850 g of a white crisp foam. NMR spectroscopy indicated a 0.25 mole % remainder of acetonitrile (calculates to be approx. 47 g) to give a true dry weight of 2803 g (96%). HPLC indicated that the product was 99.41% pure, with the remainder being 0.06 DMT-O-Me, 0.10 unknown, 0.44 bis DMT, and no detectable dimer DMT or 3′-O-DMT.  
     [0170] Preparation of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-5-methyluridin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE T Amidite)  
     [0171] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-5-methyluridine (1237 g, 2.0 mol) was dissolved in anhydrous DMF (2.5 L). The solution was co-evaporated with toluene (200 ml) at 50° C. under reduced pressure, then cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (900 g, 3.0 mol) and tetrazole (70 g, 1.0 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (20 ml) was added and the solution was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (3.5 L) and water (600 ml) and extracted with hexane (3×3L). The mixture was diluted with water (1.6 L) and extracted with the mixture of toluene (12 L) and hexanes (9 L). The upper layer was washed with DMF-water (7:3 v/v, 3×3 L) and water (3×3 L). The organic layer was dried (Na 2 SO 4 ), filtered and evaporated. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1526 g of an off-white foamy solid (95%).  
     [0172] Preparation of 5′-O-Dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methylcytidine Intermediate  
     [0173] To a 50 L Schott glass-lined steel reactor equipped with an electric stirrer, reagent addition pump (connected to an addition funnel), heating/cooling system, internal thermometer and argon gas line was added 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methyl-uridine (2.616 kg, 4.23 mol, purified by base extraction only and no scrub column), anhydrous acetonitrile (20 L), and TEA (9.5 L, 67.7 mol, 16 eq). The mixture was chilled with stirring to −10° C. internal temperature (external −20° C.). Trimethylsilylchloride (1.60 L, 12.7 mol, 3.0 eq) was added over 30 min. while maintaining the internal temperature below −5° C., followed by a wash of anhydrous acetonitrile (1 L). (Note: the reaction is mildly exothermic and copious hydrochloric acid fumes form over the course of the addition). The reaction was allowed to warm to 0° C. and the reaction progress was confirmed by TLC (EtOAc, R f  0.68 and 0.87 for starting material and silyl product, respectively). Upon completion, triazole (2.34 kg, 33.8 mol, 8.0 eq) was added the reaction was cooled to −20° C. internal temperature (external −30° C.). Phosphorous oxychloride (793 mL, 8.51 mol, 2.01 eq) was added slowly over 60 min so as to maintain the temperature between −20° C. and −10° C. (note: strongly exothermic), followed by a wash of anhydrous acetonitrile (1 L). The reaction was warmed to 0° C. and stirred for 1 h, at which point it was an off-white thick suspension. TLC indicated a complete conversion to the triazole product (EtOAc, R f  0.87 to 0.75 with the product spot glowing in long wavelength UV light). The reaction was cooled to −15° C. and water (5 L) was slowly added at a rate to maintain the temperature below +10° C. in order to quench the reaction and to form a homogenous solution. (Caution: this reaction is initially very strongly exothermic). Approximately one-half of the reaction volume (22 L) was transferred by air pump to another vessel, diluted with EtOAc (12 L) and extracted with water (2×8 L). The second half of the reaction was treated in the same way. The combined aqueous layers were back-extracted with EtOAc (8 L) The organic layers were combined and concentrated in a 20 L rotary evaporator to an oily foam. The foam was coevaporated with anhydrous acetonitrile (4 L) to remove EtOAc. (note: dioxane may be used instead of anhydrous acetonitrile if dried to a hard foam). The residue was dissolved in dioxane (2 L) and concentrated ammonium hydroxide (750 mL) was added. A homogenous solution formed in a few minutes and the reaction was allowed to stand overnight  
     [0174] TLC indicated a complete reaction (CH 2 Cl 2 -acetone-MeOH, 20:5:3, R f  0.51). The reaction solution was concentrated on a rotary evaporator to a dense foam and slowly redissolved in warm CH 2 Cl 2  (4 L, 40° C.) and transferred to a 20 L glass extraction vessel equipped with a air-powered stirrer. The organic layer was extracted with water (2×6 L) to remove the triazole by-product. (Note: In the first extraction an emulsion formed which took about 2 h to resolve). The water layer was back-extracted with CH 2 Cl 2  (2×2 L), which in turn was washed with water (3 L). The combined organic layer was concentrated in 2×20 L flasks to a gum and then recrystallized from EtOAc seeded with crystalline product. After sitting overnight, the first crop was collected on a 25 cm Coors Buchner funnel and washed repeatedly with EtOAc until a white free-flowing powder was left (about 3×3 L). The filtrate was concentrated to an oil recrystallized from EtOAc, and collected as above. The solid was air-dried in pans for 48 h, then further dried in a vacuum oven (50° C., 0.1 mm Hg, 17 h) to afford 2248 g of a bright white, dense solid (86%). An HPLC analysis indicated both crops to be 99.4% pure and NMR spectroscopy indicated only a faint trace of EtOAc remained.  
     [0175] Preparation of 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-N-4-benzoyl-5-methyl-cytidine Penultimate Intermediate:  
     [0176] Crystalline 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methyl-cytidine (1000 g, 1.62 mol) was suspended in anhydrous DMF (3 kg) at ambient temperature and stirred under an Ar atmosphere. Benzoic anhydride (439.3 g, 1.94 mol) was added in one portion. The solution clarified after 5 hours and was stirred for 16 h. HPLC indicated 0.45% starting material remained (as well as 0.32% N4, 3′-O-bis Benzoyl). An additional amount of benzoic anhydride (6.0 g, 0.0265 mol) was added and after 17 h, HPLC indicated no starting material was present. TEA (450 mL, 3.24 mol) and toluene (6 L) were added with stirring for 1 minute. The solution was washed with water (4×4 L), and brine (2×4 L). The organic layer was partially evaporated on a 20 L rotary evaporator to remove 4 L of toluene and traces of water. HPLC indicated that the bis benzoyl side product was present as a 6% impurity. The residue was diluted with toluene (7 L) and anhydrous DMSO (200 mL, 2.82 mol) and sodium hydride (60% in oil, 70 g, 1.75 mol) was added in one portion with stirring at ambient temperature over 1 h. The reaction was quenched by slowly adding then washing with aqueous citric acid (10%, 100 mL over 10 min, then 2×4 L), followed by aqueous sodium bicarbonate (2%, 2 L), water (2×4 L) and brine (4 L). The organic layer was concentrated on a 20 L rotary evaporator to about 2 L total volume. The residue was purified by silica gel column chromatography (6 L Buchner funnel containing 1.5 kg of silica gel wetted with a solution of EtOAc-hexanes-TEA (70:29:1)). The product was eluted with the same solvent (30 L) followed by straight EtOAc (6 L). The fractions containing the product were combined, concentrated on a rotary evaporator to a foam and then dried in a vacuum oven (50° C., 0.2 mm Hg, 8 h) to afford 1155 g of a crisp, white foam (98%). HPLC indicated a purity of &gt;99.7%.  
     [0177] Preparation of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 4 -benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE 5-Me-C Amidite)  
     [0178] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 4 -benzoyl-5-methylcytidine (1082 g, 1.5 mol) was dissolved in anhydrous DMF (2 L) and co-evaporated with toluene (300 ml) at 50° C. under reduced pressure. The mixture was cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (680 g, 2.26 mol) and tetrazole (52.5 g, 0.75 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (30 ml) was added, and the mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (1 L) and water (400 ml) and extracted with hexane (3×3 L). The mixture was diluted with water (1.2 L) and extracted with a mixture of toluene (9 L) and hexanes (6 L). The two layers were separated and the upper layer was washed with DMF-water (60:40 v/v, 3×3 L) and water (3×2 L). The organic layer was dried (Na 2 SO 4 ), filtered and evaporated. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1336 g of an off-white foam (97%).  
     [0179] Preparation of [5′-O— (4,4′-Dimethoxytriphenylmethyl)-2′-O— (2-methoxyethyl) —N 6 -benzoyladenosin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE A Amdite)  
     [0180] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 6 -benzoyladenosine (purchased from Reliable Biopharmaceutical, St. Lois, Mo.), 1098 g, 1.5 mol) was dissolved in anhydrous DMF (3 L) and co-evaporated with toluene (300 ml) at 50° C. The mixture was cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (680 g, 2.26 mol) and tetrazole (78.8 g, 1.24 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (30 ml) was added, and mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (1 L) and water (400 ml) and extracted with hexanes (3×3 L). The mixture was diluted with water (1.4 L) and extracted with the mixture of toluene (9 L) and hexanes (6 L). The two layers were separated and the upper layer was washed with DMF-water (60:40, v/v, 3×3 L) and water (3×2 L). The organic layer was dried (Na 2 SO 4 ), filtered and evaporated to a sticky foam. The residue was co-evaporated with acetonitrile (2.5 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1350 g of an off-white foam solid (96%).  
     [0181] Prepartion of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 4 -isobutyrylguanosin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE G Amidite)  
     [0182] 5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N 4 -isobutyrlguanosine (purchased from Reliable Biopharmaceutical, St. Louis, Mo., 1426 g, 2.0 mol) was dissolved in anhydrous DMF (2 L). The solution was co-evaporated with toluene (200 ml) at 50° C., cooled to room temperature and 2-cyanoethyl tetraisopropylphosphorodiamidite (900 g, 3.0 mol) and tetrazole (68 g, 0.97 mol) were added. The mixture was shaken until all tetrazole was dissolved, N-methylimidazole (30 ml) was added, and the mixture was left at room temperature for 5 hours. TEA (300 ml) was added, the mixture was diluted with DMF (2 L) and water (600 ml) and extracted with hexanes (3×3 L). The mixture was diluted with water (2 L) and extracted with a mixture of toluene (10 L) and hexanes (5 L). The two layers were separated and the upper layer was washed with DMF-water (60:40, v/v, 3×3 L). EtOAc (4 L) was added and the solution was washed with water (3×4 L). The organic layer was dried (Na 2 SO 4 ), filtered and evaporated to approx. 4 kg. Hexane (4 L) was added, the mixture was shaken for 10 min, and the supernatant liquid was decanted. The residue was co-evaporated with acetonitrile (2×2 L) under reduced pressure and dried in a vacuum oven (25° C., 0.1 mm Hg, 40 h) to afford 1660 g of an off-white foamy solid (91%).  
     [0183] 2′-O-(Aminooxyethyl) Nucleoside Amidites and 2′-O-(dimethylaminooxyethyl) Nucleoside Amidites  
     [0184] 2′-(Dimethylaminooxyethoxy) Nucleoside Amidites  
     [0185] 2′-(Dimethylaminooxyethoxy) nucleoside amidites (also known in the art as 2′-O-(dimethylaminooxyethyl) nucleoside amidites) are prepared as described in the following paragraphs. Adenosine, cytidine and guanosine nucleoside amidites are prepared similarly to the thymidine (5-methyluridine) except the exocyclic amines are protected with a benzoyl moiety in the case of adenosine and cytidine and with isobutyryl in the case of guanosine.  
     [0186] 5′-O-tert-Butyldiphenylsilyl-O 2 -2′-anhydro-5-methyluridine  
     [0187] O 2 -2′-anhydro-5-methyluridine (Pro. Bio. Sint., Varese, Italy, 100.0 g, 0.416 mmol), dimethylaminopyridine (0.66 g, 0.013 eq, 0.0054 mmol) were dissolved in dry pyridine (500 ml) at ambient temperature under an argon atmosphere and with mechanical stirring. tert-Butyldiphenylchlorosilane (125.8 g, 119.0 mL, 1.1 eq, 0.458 mmol) was added in one portion. The reaction was stirred for 16 h at ambient temperature. TLC (R f  0.22, EtOAc) indicated a complete reaction. The solution was concentrated under reduced pressure to a thick oil. This was partitioned between CH 2 Cl 2  (1 L) and saturated sodium bicarbonate (2×1 L) and brine (1 L). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to a thick oil. The oil was dissolved in a 1:1 mixture of EtOAc and ethyl ether (600 mL) and cooling the solution to −10° C. afforded a white crystalline solid which was collected by filtration, washed with ethyl ether (3×200 mL) and dried (40° C., 1 mm Hg, 24 h) to afford 149 g of white solid (74.8%). TLC and NMR spectroscopy were consistent with pure product.  
     [0188] 5′-O-tert-Butyldiphenylsilyl-2′-O-(2-hydroxyethyl)-5-methyluridine  
     [0189] In the fume hood, ethylene glycol (350 mL, excess) was added cautiously with manual stirring to a 2 L stainless steel pressure reactor containing borane in tetrahydrofuran (1.0 M, 2.0 eq, 622 mL). (Caution: evolves hydrogen gas). 5′-O-tert-Butyldiphenylsilyl-O 2-2′-anhydro-5-methyluridine (149 g, 0.311 mol) and sodium bicarbonate (0.074 g, 0.003 eq) were added with manual stirring. The reactor was sealed and heated in an oil bath until an internal temperature of 160° C. was reached and then maintained for 16 h (pressure &lt;100 psig). The reaction vessel was cooled to ambient temperature and opened. TLC (EtOAc, R f  0.67 for desired product and R f  0.82 for ara-T side product) indicated about 70% conversion to the product. The solution was concentrated under reduced pressure (10 to 1 mm Hg) in a warm water bath (40-100° C.) with the more extreme conditions used to remove the ethylene glycol. (Alternatively, once the THF has evaporated the solution can be diluted with water and the product extracted into EtOAc). The residue was purified by column chromatography (2 kg silica gel, EtOAc-hexanes gradient 1:1 to 4:1). The appropriate fractions were combined, evaporated and dried to afford 84 g of a white crisp foam (50%), contaminated starting material (17.4 g, 12% recovery) and pure reusable starting material (20 g, 13% recovery). TLC and NMR spectroscopy were consistent with 99% pure product.  
     [0190] 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine  
     [0191] 5′-O-tert-Butyldiphenylsilyl-2′-O-(2-hydroxyethyl)-5-methyluridine (20 g, 36.98 mmol) was mixed with triphenylphosphine (11.63 g, 44.36 mmol) and N-hydroxyphthalimide (7.24 g, 44.36 mmol) and dried over P 2 O 5  under high vacuum for two days at 40° C. The reaction mixture was flushed with argon and dissolved in dry THF (369.8 mL, Aldrich, sure seal bottle). Diethyl-azodicarboxylate (6.98 mL, 44.36 mmol) was added dropwise to the reaction mixture with the rate of addition maintained such that the resulting deep red coloration is just discharged before adding the next drop. The reaction mixture was stirred for 4 hrs., after which time TLC (EtOAc:hexane, 60:40) indicated that the reaction was complete. The solvent was evaporated in vacuuo and the residue purified by flash column chromatography (eluted with 60:40 EtOAc:hexane), to yield 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphen-ylsilyl-5-methyluridine as white foam (21.819 g, 86%) upon rotary evaporation.  
     [0192] 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy)ethyl]-5-methyluridine  
     [0193] 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine (3.1 g, 4.5 mmol) was dissolved in dry CH 2 Cl 2  (4.5 mL) and methylhydrazine (300 mL, 4.64 mmol) was added dropwise at −10° C. to 0° C. After 1 h the mixture was filtered, the filtrate washed with ice cold CH 2 Cl 2 , and the combined organic phase was washed with water and brine and dried (anhydrous Na 2 SO 4 ). The solution was filtered and evaporated to afford 2′-O-(aminooxyethyl) thymidine, which was then dissolved in MeOH (67.5 mL). Formaldehyde (20% aqueous solution, w/w, 1.1 eq.) was added and the resulting mixture was stirred for 1 h. The solvent was removed under vacuum and the residue was purified by column chromatography to yield 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy) ethyl]-5-methyluridine as white foam (1.95 g, 78%) upon rotary evaporation.  
     [0194] 5′-O-tert-Butyldiphenylsilyl-2′-O-[N,N Dimethylaminooxyethyl]-5-methyluridine  
     [0195] 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy)ethyl]-5-methyluridine (1.77 g, 3.12 mmol) was dissolved in a solution of 1M pyridinium p-toluenesulfonate (PPTS) in dry MeOH (30.6 mL) and cooled to 10° C. under inert atmosphere. Sodium cyanoborohydride (0.39 g, 6.13 mmol) was added and the reaction mixture was stirred. After 10 minutes the reaction was warmed to room temperature and stirred for 2 h. while the progress of the reaction was monitored by TLC (5% MeOH in CH 2 Cl 2 ). Aqueous NaHCO 3  solution (5%, 10 mL) was added and the product was extracted with EtOAc (2×20 mL). The organic phase was dried over anhydrous Na 2 SO 4 , filtered, and evaporated to dryness. This entire procedure was repeated with the resulting residue, with the exception that formaldehyde (20% w/w, 30 mL, 3.37 mol) was added upon dissolution of the residue in the PPTS/MeOH solution. After the extraction and evaporation, the residue was purified by flash column chromatography and (eluted with 5% MeOH in CH 2 Cl 2 ) to afford 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine as a white foam (14.6 g, 80%) upon rotary evaporation.  
     [0196] 2′-O-(dimethylaminooxyethyl)-5-methyluridine  
     [0197] Triethylamine trihydrofluoride (3.91 mL, 24.0 mmol) was dissolved in dry THF and TEA (1.67 mL, 12 mmol, dry, stored over KOH) and added to 5′-O-tert-butyldiphenylsilyl-2′-O-[N,N-dimethylaminooxyethyl]-5-methyluridine (1.40 g, 2.4 mmol). The reaction was stirred at room temperature for 24 hrs and monitored by TLC (5% MeOH in CH 2 Cl 2 ). The solvent was removed under vacuum and the residue purified by flash column chromatography (eluted with 10% MeOH in CH 2 Cl 2 ) to afford 2′-O-(dimethylaminooxyethyl)-5-methyluridine (766 mg, 92.5%) upon rotary evaporation of the solvent.  
     [0198] 5′-O-DMT-2′-O-(dimethylaminooxyethyl)-5-methyluridine  
     [0199] 2′-O-(dimethylaminooxyethyl)-5-methyluridine (750 mg, 2.17 mmol) was dried over P 2 O 5  under high vacuum overnight at 40° C., co-evaporated with anhydrous pyridine (20 mL), and dissolved in pyridine (11 mL) under argon atmosphere. 4-dimethylaminopyridine (26.5 mg, 2.60 mmol) and 4,4′-dimethoxytrityl chloride (880 mg, 2.60 mmol) were added to the pyridine solution and the reaction mixture was stirred at room temperature until all of the starting material had reacted. Pyridine was removed under vacuum and the residue was purified by column chromatography (eluted with 10% MeOH in CH 2 Cl 2  containing a few drops of pyridine) to yield 5′-O-DMT-2′-O-(dimethylamino-oxyethyl)-5-methyluridine (1.13 g, 80%) upon rotary evaporation.  
     [0200] 5′-O-DMT-2′-O-(2-N,N-dimethylaminooxyethyl)-5-methyluridine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] 
     [0201] 5′-O-DMT-2′-O-(dimethylaminooxyethyl)-5-methyluridine (1.08 g, 1.67 mmol) was co-evaporated with toluene (20 mL), N,N-diisopropylamine tetrazonide (0.29 g, 1.67 mmol) was added and the mixture was dried over P 2 O 5  under high vacuum overnight at 40° C. This was dissolved in anhydrous acetonitrile (8.4 mL) and 2-cyanoethyl-N,N,N 1 ,N 1 -tetraisopropylphosphoramidite (2.12 mL, 6.08 mmol) was added. The reaction mixture was stirred at ambient temperature for 4 h under inert atmosphere. The progress of the reaction was monitored by TLC (hexane:EtOAc 1:1). The solvent was evaporated, then the residue was dissolved in EtOAc (70 mL) and washed with 5% aqueous NaHCO 3  (40 mL). The EtOAc layer was dried over anhydrous Na 2 SO 4 , filtered, and concentrated. The residue obtained was purified by column chromatography (EtOAc as eluent) to afford 5′-O-DMT-2′-O-(2-N,N-dimethylaminooxyethyl)-5-methyluridine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] as a foam (1.04 g, 74.9%) upon rotary evaporation.  
     [0202] 2′-(Aminooxyethoxy) Nucleoside Amidites  
     [0203] 2′-(Aminooxyethoxy) nucleoside amidites (also known in the art as 2′-O-(aminooxyethyl) nucleoside amidites) are prepared as described in the following paragraphs. Adenosine, cytidine and thymidine nucleoside amidites are prepared similarly.  
     [0204] N2-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] 
     [0205] The 2′-O-aminooxyethyl guanosine analog may be obtained by selective 2′-O-alkylation of diaminopurine riboside. Multigram quantities of diaminopurine riboside may be purchased from Schering AG (Berlin) to provide 2′-O-(2-ethylacetyl) diaminopurine riboside along with a minor amount of the 3′-O-isomer. 2′-O-(2-ethylacetyl) diaminopurine riboside may be resolved and converted to 2′-O-(2-ethylacetyl)guanosine by treatment with adenosine deaminase. (McGee, D. P. C., Cook, P. D., Guinosso, C. J., WO 94/02501 A1 940203.) Standard protection procedures should afford 2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine and 2-N-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine which may be reduced to provide 2-N-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-hydroxyethyl)-5′-O-(4,4′-dimethoxytrityl)guanosine. As before the hydroxyl group may be displaced by N-hydroxyphthalimide via a Mitsunobu reaction, and the protected nucleoside may be phosphitylated as usual to yield 2-N-isobutyryl-6-O-diphenylcarbamoyl-2′-O-([2-phthalmidoxy]ethyl)-5′-O-(4,4′-dimethoxytrityl)guanosine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite].  
     [0206] 2′-dimethylaminoethoxyethoxy (2′-DMAEOE) Nucleoside Amidites  
     [0207] 2′-dimethylaminoethoxyethoxy nucleoside amidites (also known in the art as 2′-O-dimethylaminoethoxyethyl, i.e., 2′-O—CH 2 —O—CH 2 —N(CH 2 ) 2 , or 2′-DMAEOE nucleoside amidites) are prepared as follows. Other nucleoside amidites are prepared similarly.  
     [0208] 2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl]-5-methyl Uridine  
     [0209] 2[2-(Dimethylamino)ethoxy]ethanol (Aldrich, 6.66 g, 50 mmol) was slowly added to a solution of borane in tetrahydrofuran (1 M, 10 mL, 10 mmol) with stirring in a 100 mL bomb. (Caution: Hydrogen gas evolves as the solid dissolves). O 2 -,2′-anhydro-5-methyluridine (1.2 g, 5 mmol), and sodium bicarbonate (2.5 mg) were added and the bomb was sealed, placed in an oil bath and heated to 155° C. for 26 h. then cooled to room temperature. The crude solution was concentrated, the residue was diluted with water (200 mL) and extracted with hexanes (200 mL). The product was extracted from the aqueous layer with EtOAc (3×200 mL) and the combined organic layers were washed once with water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (eluted with 5:100:2 MeOH/CH 2 Cl 2 /TEA) as the eluent. The appropriate fractions were combined and evaporated to afford the product as a white solid.  
     [0210] 5′-O-dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy) ethyl)]-5-methyl Uridine  
     [0211] To 0.5 g (1.3 mmol) of 2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl)]-5-methyl uridine in anhydrous pyridine (8 mL), was added TEA (0.36 mL) and dimethoxytrityl chloride (DMT-Cl, 0.87 g, 2 eq.) and the reaction was stirred for 1 h. The reaction mixture was poured into water (200 mL) and extracted with CH 2 Cl 2  (2×200 mL). The combined CH 2 Cl 2  layers were washed with saturated NaHCO 3  solution, followed by saturated NaCl solution, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (eluted with 5:100:1 MeOH/CH 2 Cl 2 /TEA) to afford the product.  
     [0212] 5′-O-Dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl)]-5-methyl Uridine-3′-O-(cyanoethyl-N,N-diisopropyl)phosphoramidite  
     [0213] Diisopropylaminotetrazolide (0.6 g) and 2-cyanoethoxy-N,N-diisopropyl phosphoramidite (1.1 mL, 2 eq.) were added to a solution of 5′-O-dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl)]-5-methyluridine (2.17 g, 3 mmol) dissolved in CH 2 Cl 2  (20 mL) under an atmosphere of argon. The reaction mixture was stirred overnight and the solvent evaporated. The resulting residue was purified by silica gel column chromatography with EtOAc as the eluent to afford the title compound.  
     Example 2  
     [0214] Oligonucleotide Synthesis  
     [0215] Unsubstituted and substituted phosphodiester (P═O) oligonucleotides are synthesized on an automated DNA synthesizer (Applied Biosystems model 394) using standard phosphoramidite chemistry with oxidation by iodine.  
     [0216] Phosphorothioates (P═S) are synthesized similar to phosphodiester oligonucleotides with the following exceptions: thiation was effected by utilizing a 10% w/v solution of 3H-1,2-benzodithiole-3-one 1,1-dioxide in acetonitrile for the oxidation of the phosphite linkages. The thiation reaction step time was increased to 180 sec and preceded by the normal capping step. After cleavage from the CPG column and deblocking in concentrated ammonium hydroxide at 55° C. (12-16 hr), the oligonucleotides were recovered by precipitating with &gt;3 volumes of ethanol from a 1 M NH 4 oAc solution. Phosphinate oligonucleotides are prepared as described in U.S. Pat. No. 5,508,270, herein incorporated by reference.  
     [0217] Alkyl phosphonate oligonucleotides are prepared as described in U.S. Pat. No. 4,469,863, herein incorporated by reference.  
     [0218] 3′-Deoxy-3′-methylene phosphonate oligonucleotides are prepared as described in U.S. Pat. No. 5,610,289 or 5,625,050, herein incorporated by reference.  
     [0219] Phosphoramidite oligonucleotides are prepared as described in U.S. Pat. No. 5,256,775 or 5,366,878, herein incorporated by reference.  
     [0220] Alkylphosphonothioate oligonucleotides are prepared as described in published PCT applications PCT/US94/00902 and PCT/US93/06976 (published as WO 94/17093 and WO 94/02499, respectively), herein incorporated by reference.  
     [0221] 3′-Deoxy-3′-amino phosphoramidate oligonucleotides are prepared as described in U.S. Pat. No. 5,476,925, herein incorporated by reference.  
     [0222] Phosphotriester oligonucleotides are prepared as described in U.S. Pat. No. 5,023,243, herein incorporated by reference.  
     [0223] Borano phosphate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,130,302 and 5,177,198, both herein incorporated by reference.  
     Example 3  
     [0224] Oligonucleoside Synthesis  
     [0225] Methylenemethylimino linked oligonucleosides, also identified as MMI linked oligonucleosides, methylenedimethylhydrazo linked oligonucleosides, also identified as MDH linked oligonucleosides, and methylenecarbonylamino linked oligonucleosides, also identified as amide-3 linked oligonucleosides, and methyleneaminocarbonyl linked oligonucleosides, also identified as amide-4 linked oligonucleosides, as well as mixed backbone compounds having, for instance, alternating MMI and P═O or P═S linkages are prepared as described in U.S. Pat. Nos. 5,378,825, 5,386,023, 5,489,677, 5,602,240 and 5,610,289, all of which are herein incorporated by reference.  
     [0226] Formacetal and thioformacetal linked oligonucleosides are prepared as described in U.S. Pat. Nos. 5,264,562 and 5,264,564, herein incorporated by reference.  
     [0227] Ethylene oxide linked oligonucleosides are prepared as described in U.S. Pat. No. 5,223,618, herein incorporated by reference.  
     Example 4  
     [0228] PNA Synthesis  
     [0229] Peptide nucleic acids (PNAs) are prepared in accordance with any of the various procedures referred to in Peptide Nucleic Acids (PNA): Synthesis, Properties and Potential Applications,  Bioorganic  &amp;  Medicinal Chemistry,  1996, 4, 5-23. They may also be prepared in accordance with U.S. Pat. Nos. 5,539,082, 5,700,922, and 5,719,262, herein incorporated by reference.  
     Example 5  
     [0230] Synthesis of Chimeric Oligonucleotides  
     [0231] Chimeric oligonucleotides, oligonucleosides or mixed oligonucleotides/oligonucleosides of the invention can be of several different types. These include a first type wherein the “gap” segment of linked nucleosides is positioned between 5′ and 3′ “wing” segments of linked nucleosides and a second “open end” type wherein the “gap” segment is located at either the 3′ or the 5′ terminus of the oligomeric compound. Oligonucleotides of the first type are also known in the art as “gapmers” or gapped oligonucleotides. Oligonucleotides of the second type are also known in the art as “hemimers” or “wingmers”.  
     [0232] [2′-O-Me]--[2′-deoxy]--[2′-O-Me] Chimeric Phosphorothioate Oligonucleotides  
     [0233] Chimeric oligonucleotides having 2′-O-alkyl phosphorothioate and 2′-deoxy phosphorothioate oligonucleotide segments are synthesized using an Applied Biosystems automated DNA synthesizer Model 394, as above. Oligonucleotides are synthesized using the automated synthesizer and 2′-deoxy-5′-dimethoxytrityl-3′--O-phosphoramidite for the DNA portion and 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite for 5′ and 3′ wings. The standard synthesis cycle is modified by incorporating coupling steps with increased reaction times for the 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite. The fully protected oligonucleotide is cleaved from the support and deprotected in concentrated ammonia (NH 4 OH) for 12-16 hr at 55° C. The deprotected oligo is then recovered by an appropriate method (precipitation, column chromatography, volume reduced in vacuo and analyzed spetrophotometrically for yield and for purity by capillary electrophoresis and by mass spectrometry.  
     [0234] [2′-O-(2-Methoxyethyl)]--[2′-deoxy]--[2′-O-(Methoxyethyl)] Chimeric Phosphorothioate Oligonucleotides  
     [0235] [2′-O-(2-methoxyethyl)]--[2′-deoxy]--[-2′-O-(methoxyethyl)] chimeric phosphorothioate oligonucleotides were prepared as per the procedure above for the 2′-O-methyl chimeric oligonucleotide, with the substitution of 2′-O-(methoxyethyl) amidites for the 2′-O-methyl amidites.  
     [0236] [2′-O-(2-Methoxyethyl)Phosphodiester]--[2′-deoxy Phosphorothioate]--[2′-O-(2-Methoxyethyl) Phosphodiester] Chimeric Oligonucleotides  
     [0237] [2′-O-(2-methoxyethyl phosphodiester]--[2′-deoxy phosphorothioate]--[2′-O-(methoxyethyl) phosphodiester] chimeric oligonucleotides are prepared as per the above procedure for the 2′-O-methyl chimeric oligonucleotide with the substitution of 2′-O-(methoxyethyl) amidites for the 2′-O-methyl amidites, oxidation with iodine to generate the phosphodiester internucleotide linkages within the wing portions of the chimeric structures and sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) to generate the phosphorothioate internucleotide linkages for the center gap.  
     [0238] Other chimeric oligonucleotides, chimeric oligonucleosides and mixed chimeric oligonucleotides/oligonucleosides are synthesized according to U.S. Pat. No. 5,623,065, herein incorporated by reference.  
     Example 6  
     [0239] Oligonucleotide Isolation  
     [0240] After cleavage from the controlled pore glass solid support and deblocking in concentrated ammonium hydroxide at 55° C. for 12-16 hours, the oligonucleotides or oligonucleosides are recovered by precipitation out of 1 M NH 4 OAc with &gt;3 volumes of ethanol. Synthesized oligonucleotides were analyzed by electrospray mass spectroscopy (molecular weight determination) and by capillary gel electrophoresis and judged-to be at least 70% full length material. The relative amounts of phosphorothioate and phosphodiester linkages obtained in the synthesis was determined by the ratio of correct molecular weight relative to the −16 amu product (+/−32+/−48). For some studies oligonucleotides were purified by HPLC, as described by Chiang et al.,  J. Biol. Chem.  1991, 266, 18162-18171. Results obtained with HPLC-purified material were similar to those obtained with non-HPLC purified material.  
     Example 7  
     [0241] Oligonucleotide Synthesis—96 Well Plate Format  
     [0242] Oligonucleotides were synthesized via solid phase P(III) phosphoramidite chemistry on an automated synthesizer capable of assembling 96 sequences simultaneously in a 96-well format. Phosphodiester internucleotide linkages were afforded by oxidation with aqueous iodine. Phosphorothioate internucleotide linkages were generated by sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) in anhydrous acetonitrile. Standard base-protected beta-cyanoethyl-diiso-propyl phosphoramidites were purchased from commercial vendors (e.g. PE-Applied Biosystems, Foster City, Calif., or Pharmacia, Piscataway, N.J.). Non-standard nucleosides are synthesized as per standard or patented methods. They are utilized as base protected beta-cyanoethyldiisopropyl phosphoramidites.  
     [0243] Oligonucleotides were cleaved from support and deprotected with concentrated NH 4 OH at elevated temperature (55-60° C.) for 12-16 hours and the released product then dried in vacuo. The dried product was then re-suspended in sterile water to afford a master plate from which all analytical and test plate samples are then diluted utilizing robotic pipettors.  
     Example 8  
     [0244] Oligonucleotide Analysis—96-Well Plate Format  
     [0245] The concentration of oligonucleotide in each well was assessed by dilution of samples and UV absorption spectroscopy. The full-length integrity of the individual products was evaluated by capillary electrophoresis (CE) in either the 96-well format (Beckman P/ACE™ MDQ) or, for individually prepared samples, on a commercial CE apparatus (e.g., Beckman P/ACE™ 5000, ABI 270). Base and backbone composition was confirmed by mass analysis of the compounds utilizing electrospray-mass spectroscopy. All assay test plates were diluted from the master plate using single and multi-channel robotic pipettors. Plates were judged to be acceptable if at least 85% of the compounds on the plate were at least 85% full length.  
     Example 9  
     [0246] Cell Culture and Oligonucleotide Treatment  
     [0247] The effect of antisense compounds on target nucleic acid expression can be tested in any of a variety of cell types provided that the target nucleic acid is present at measurable levels. This can be routinely determined using, for example, PCR or Northern blot analysis. The following cell types are provided for illustrative purposes, but other cell types can be routinely used, provided that the target is expressed in the cell type chosen. This can be readily determined by methods routine in the art, for example Northern blot analysis, ribonuclease protection assays, or RT-PCR.  
     [0248] T-24 Cells:  
     [0249] The human transitional cell bladder carcinoma cell line T-24 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). T-24 cells were routinely cultured in complete McCoy&#39;s 5A basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence. Cells were seeded into 96-well plates (Falcon-Primaria #3872) at a density of 7000 cells/well for use in RT-PCR analysis.  
     [0250] For Northern blotting or other analysis, cells may be seeded onto 100 mm or other standard tissue culture plates and treated similarly, using appropriate volumes of medium and oligonucleotide.  
     [0251] A549 Cells:  
     [0252] The human lung carcinoma cell line A549 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). A549 cells were routinely cultured in DMEM basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence.  
     [0253] NHDF Cells:  
     [0254] Human neonatal dermal fibroblast (NHDF) were obtained from the Clonetics Corporation (Walkersville, Md.). NHDFs were routinely maintained in Fibroblast Growth Medium (Clonetics Corporation, Walkersville, Md.) supplemented as recommended by the supplier. Cells were maintained for up to 10 passages as recommended by the supplier.  
     [0255] HEK Cells:  
     [0256] Human embryonic keratinocytes (HEK) were obtained from the Clonetics Corporation (Walkersville, Md.). HEKs were routinely maintained in Keratinocyte Growth Medium (Clonetics Corporation, Walkersville, Md.) formulated as recommended by the supplier. Cells were routinely maintained for up to 10 passages as recommended by the supplier.  
     [0257] Treatment with Antisense Compounds:  
     [0258] When cells reached 70% confluency, they were treated with oligonucleotide. For cells grown in 96-well plates, wells were washed once with 100 μL OPTI-MEM™-1 reduced-serum medium (Invitrogen Corporation, Carlsbad, Calif.) and then treated with 130 μL of OPTI-MEM™-1 containing 3.75 μg/mL LIPOFECTIN™ (Invitrogen Corporation, Carlsbad, Calif.) and the desired concentration of oligonucleotide. After 4-7 hours of treatment, the medium was replaced with fresh medium. Cells were harvested 16-24 hours after oligonucleotide treatment.  
     [0259] The concentration of oligonucleotide used varies from cell line to cell line. To determine the optimal oligonucleotide concentration for a particular cell line, the cells are treated with a positive control oligonucleotide at a range of concentrations. For human cells the positive control oligonucleotide is selected from either ISIS 13920 (TCCGTCATCGCTCCTCAGGG, SEQ ID NO: 1) which is targeted to human H-ras, or ISIS 18078, (GTGCGCGCGAGCCCGAAATC, SEQ ID NO: 2) which is targeted to human Jun-N-terminal kinase-2 (JNK2). Both controls are 2′-O-methoxyethyl gapmers (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone. For mouse or rat cells the positive control oligonucleotide is ISIS 15770, ATGCATTCTGCCCCCAAGGA, SEQ ID NO: 3, a 2′-O-methoxyethyl gapmer (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone which is targeted to both mouse and rat c-raf. The concentration of positive control oligonucleotide that results in 80% inhibition of c-Ha-ras (for ISIS 13920) or c-raf (for ISIS 15770) mRNA is then utilized as the screening concentration for new oligonucleotides in subsequent experiments for that cell line. If 80% inhibition is not achieved, the lowest concentration of positive control oligonucleotide that results in 60% inhibition of H-ras or c-raf mRNA is then utilized as the oligonucleotide screening concentration in subsequent experiments for that cell line. If 60% inhibition is not achieved, that particular cell line is deemed as unsuitable for oligonucleotide transfection experiments. The concentrations of antisense oligonucleotides used herein are from 50 nM to 300 nM.  
     Example 10  
     [0260] Analysis of Oligonucleotide Inhibition of PAZ/PIWI Domain-Containing Protein Expression  
     [0261] Antisense modulation of PAZ/PIWI domain-containing protein expression can be assayed in a variety of ways known in the art. For example, PAZ/PIWI domain-containing protein mRNA levels can be quantitated by, e.g., Northern blot analysis, competitive polymerase chain reaction (PCR), or real-time PCR (RT-PCR). Real-time quantitative PCR is presently preferred. RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. The preferred method of RNA analysis of the present invention is the use of total cellular RNA as described in other examples herein. Methods of RNA isolation are taught in, for example, Ausubel, F. M. et al.,  Current Protocols in Molecular Biology,  Volume 1, pp. 4.1.1-4.2.9 and 4.5.1-4.5.3, John Wiley &amp; Sons, Inc., 1993. Northern blot analysis is routine in the art and is taught in, for example, Ausubel, F. M. et al.,  Current Protocols in Molecular Biology,  Volume 1, pp. 4.2.1-4.2.9, John Wiley &amp; Sons, Inc., 1996. Real-time quantitative (PCR) can be conveniently accomplished using the commercially available ABI PRISM™ 7700 Sequence Detection System, available from PE-Applied Biosystems, Foster City, Calif. and used according to manufacturer&#39;s instructions.  
     [0262] Protein levels of PAZ/PIWI domain-containing protein can be quantitated in a variety of ways well known in the art, such as immunoprecipitation, Western blot analysis (immunoblotting), ELISA or fluorescence-activated cell sorting (FACS). Antibodies directed to PAZ/PIWI domain-containing protein can be identified and obtained from a variety of sources, such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, Mich.), or can be prepared via conventional antibody generation methods. Methods for preparation of polyclonal antisera are taught in, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 11.12.1-11.12.9, John Wiley &amp; Sons, Inc., 1997). Preparation of monoclonal antibodies is taught in, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 11.4.1-11.11.5, John Wiley &amp; Sons, Inc., 1997).  
     [0263] Immunoprecipitation methods are standard in the art and can be found at, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 10.16.1-10.16.11, John Wiley &amp; Sons, Inc., 1998). Western blot (immunoblot) analysis is standard in the art and can be found at, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 10.8.1-10.8.21, John Wiley &amp; Sons, Inc., 1997). Enzyme-linked immunosorbent assays (ELISA) are standard in the art and can be found at, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 2, pp. 11.2.1-11.2.22, John Wiley-&amp; Sons, Inc., 1991).  
     Example 11  
     [0264] Poly(A)+ mRNA Isolation  
     [0265] Poly(A)+ mRNA was isolated according to Miura et al., ( Clin. Chem.,  1996, 42, 1758-1764). Other methods for poly(A)+ mRNA isolation are taught in, for example, Ausubel, F. M. et al., ( Current Protocols in Molecular Biology,  Volume 1, pp. 4.5.1-4.5.3, John Wiley &amp; Sons, Inc., 1993). Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 60 μL lysis buffer (10 mM Tris-HCl, pH 7.6, 1 mM EDTA, 0.5 M NaCl, 0.5% NP-40, 20 mM vanadyl-ribonucleoside complex) was added to each well, the plate was gently agitated and then incubated at room temperature for five minutes. 55 μL of lysate was transferred to Oligo d(T) coated 96-well plates (AGCT Inc., Irvine Calif.). Plates were incubated for 60 minutes at room temperature, washed 3 times with 200 μL of wash buffer (10 mM Tris-HCl pH 7.6, 1 mM EDTA, 0.3 M NaCl). After the final wash, the plate was blotted on paper towels to remove excess wash buffer and then air-dried for 5 minutes. 60 μL of elution buffer (5 mM Tris-HCl pH 7.6), preheated to 70° C., was added to each well, the plate was incubated on a 90° C. hot plate for 5 minutes, and the eluate was then transferred to a fresh 96-well plate.  
     [0266] Cells grown on 100 mm or other standard plates may be treated similarly, using appropriate volumes of all solutions.  
     Example 12  
     [0267] Total RNA Isolation  
     [0268] Total RNA was isolated using an RNEASY 96™ kit and buffers purchased from Qiagen Inc. (Valencia, Calif.) following the manufacturer&#39;s recommended procedures. Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 150 μL Buffer RLT was added to each well and the plate vigorously agitated for 20 seconds. 150 μL of 70% ethanol was then added to each well and the contents mixed by pipetting three times up and down. The samples were then transferred to the RNEASY 96™ well plate attached to a QIAVAC™ manifold fitted with a waste collection tray and attached to a vacuum source. Vacuum was applied for 1 minute. 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and incubated for 15 minutes and the vacuum was again applied for 1 minute. An additional 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and the vacuum was applied for 2 minutes. 1 mL of Buffer RPE was then added to each well of the RNEASY 96™ plate and the vacuum applied for a period of 90 seconds. The Buffer RPE wash was then repeated and the vacuum was applied for an additional 3 minutes. The plate was then removed from the QIAVAC™ manifold and blotted dry on paper towels. The plate was then re-attached to the QIAVAC™ manifold fitted with a collection tube rack containing 1.2 mL collection tubes. RNA was then eluted by pipetting 170 μL water into each well, incubating 1 minute, and then applying the vacuum for 3 minutes.  
     [0269] The repetitive pipetting and elution steps may be automated using a QIAGEN Bio-Robot 9604 (Qiagen, Inc., Valencia Calif.). Essentially, after lysing of the cells on the culture plate, the plate is transferred to the robot deck where the pipetting, DNase treatment and elution steps are carried out.  
     Example 13  
     [0270] Real-Time Quantitative PCR Analysis of PAZ/PIWI Domain-Containing Protein mRNA Levels  
     [0271] Quantitation of PAZ/PIWI domain-containing protein mRNA levels was determined by real-time quantitative PCR using the ABI PRISM™ 7700 Sequence Detection System (PE-Applied Biosystems, Foster City, Calif.) according to manufacturer&#39;s instructions. This is a closed-tube, non-gel-based, fluorescence detection system which allows high-throughput quantitation of polymerase chain reaction (PCR) products in real-time. As opposed to standard PCR in which amplification products are quantitated after the PCR is completed, products in real-time quantitative PCR are quantitated as they accumulate. This is accomplished by including in the PCR reaction an oligonucleotide probe that anneals specifically between the forward and reverse PCR primers, and contains two fluorescent dyes. A reporter dye (e.g., FAM or JOE, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, Iowa) is attached to the 5′ end of the probe and a quencher dye (e.g., TAMRA, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, Iowa) is attached to the 3′ end of the probe. When the probe and dyes are intact, reporter dye emission is quenched by the proximity of the 3′ quencher dye. During amplification, annealing of the probe to the target sequence creates a substrate that can be cleaved by the 5′-exonuclease activity of Taq polymerase. During the extension phase of the PCR amplification cycle, cleavage of the probe by Taq polymerase releases the reporter dye from the remainder of the probe (and hence from the quencher moiety) and a sequence-specific fluorescent signal is generated. With each cycle, additional reporter dye molecules are cleaved from their respective probes, and the fluorescence intensity is monitored at regular intervals by laser optics built into the ABI PRISM™ 7700 Sequence Detection System. In each assay, a series of parallel reactions containing serial dilutions of mRNA from untreated control samples generates a standard curve that is used to quantitate the percent inhibition after antisense oligonucleotide treatment of test samples.  
     [0272] Prior to quantitative PCR analysis, primer-probe sets specific to the target gene being measured are evaluated for their ability to be “multiplexed” with a GAPDH amplification reaction. In multiplexing, both the target gene and the internal standard gene GAPDH are amplified concurrently in a single sample. In this analysis, mRNA isolated from untreated cells is serially diluted. Each dilution is amplified in the presence of primer-probe sets specific for GAPDH only, target gene only (“single-plexing”), or both (multiplexing). Following PCR amplification, standard curves of GAPDH and target mRNA signal as a function of dilution are generated from both the single-plexed and multiplexed samples. If both the slope and correlation coefficient of the GAPDH and target signals generated from the multiplexed samples fall within 10% of their corresponding values generated from the single-plexed samples, the primer-probe set specific for that target is deemed multiplexable. Other methods of PCR are also known in the art.  
     [0273] PCR reagents were obtained from Invitrogen Corporation, (Carlsbad, Calif.). RT-PCR reactions were carried out by adding 20 μL PCR cocktail (2.5×PCR buffer (—MgCl2), 6.6 mM MgCl2, 375 μM each of DATP, dCTP, dCTP and dGTP, 375 nM each of forward primer and reverse primer, 125 μM of probe, 4 Units RNAse inhibitor, 1.25 Units PLATINUM® Taq, 5 Units MuLV reverse transcriptase, and 2.5×ROX dye) to 96-well plates containing 30 μL total RNA solution. The RT reaction was carried out by incubation for 30 minutes at 48° C. Following a 10 minute incubation at 95° C. to activate the PLATINUM® Taq, 40 cycles of a two-step PCR protocol were carried out: 95° C. for 15 seconds (denaturation) followed by 60° C. for 1.5 minutes (annealing/extension).  
     [0274] Gene target quantities obtained by real time RT-PCR are normalized using either the expression level of GAPDH, a gene whose expression is constant, or by quantifying total RNA using RiboGreen™ (Molecular Probes, Inc. Eugene, Oreg.). GAPDH expression is quantified by real time RT-PCR, by being run simultaneously with the target, multiplexing, or separately. Total RNA is quantified using RiboGreen™ RNA quantification reagent from Molecular Probes. Methods of RNA quantification by RiboGreen™ are taught in Jones, L. J., et al, (Analytical Biochemistry, 1998, 265, 368-374).  
     [0275] In this assay, 170 μL of RiboGreen™ working reagent (RiboGreen™ reagent diluted 1:350 in 10 mM Tris-HCl, 1 mM EDTA, pH 7.5) is pipetted into a 96-well plate containing 30 μL purified, cellular RNA. The plate is read in a CytoFluor 4000 (PE Applied Biosystems) with excitation at 480 nm and emission at 520 nm.  
     [0276] Probes and primers to human PAZ/PIWI domain-containing protein were designed to hybridize to a human PAZ/PIWI domain-containing protein sequence, using published sequence information (GenBank accession number NM — 024852.1, incorporated herein as SEQ ID NO:4). For human PAZ/PIWI domain-containing protein the PCR primers were: forward primer: AAATTTGTCTCTCGGGTGAGTTG (SEQ ID NO: 5) reverse primer: TTAGTGCTGATTGGCTTGTCTAATTC (SEQ ID NO: 6) and the PCR probe was: FAM-AGTACTGACAGGACGGACTTTGCCT-TAMRA (SEQ ID NO: 7) where FAM is the fluorescent dye and TAMRA is the quencher dye. For human GAPDH the PCR primers were: forward primer: GAAGGTGAAGGTCGGAGTC (SEQ ID NO:8) reverse primer: GAAGATGGTGATGGGATTTC (SEQ ID NO:9) and the PCR probe was: 5′ JOE-CAAGCTTCCCGTTCTCAGCC— TAMRA 3′ (SEQ ID NO: 10) where JOE is the fluorescent reporter dye and TAMRA is the quencher dye.  
     Example 14  
     [0277] Northern Blot Analysis of PAZ/PIWI Domain-Containing Protein mRNA Levels  
     [0278] Eighteen hours after antisense treatment, cell monolayers were washed twice with cold PBS and lysed in 1 mL RNAZOL™ (TEL-TEST “B” Inc., Friendswood, Tex.). Total RNA was prepared following manufacturer&#39;s recommended protocols. Twenty micrograms of total RNA was fractionated by electrophoresis through 1.2% agarose gels containing 1.1% formaldehyde using a MOPS buffer system (AMRESCO, Inc. Solon, Ohio). RNA was transferred from the gel to HYBOND™-N+ nylon membranes (Amersham Pharmacia Biotech, Piscataway, N.J.) by overnight capillary transfer using a Northern/Southern Transfer buffer system (TEL-TEST “B” Inc., Friendswood, Tex.). RNA transfer was confirmed by UV visualization. Membranes were fixed by UV cross-linking using a STRATALINKER™ UV Crosslinker 2400 (Stratagene, Inc, La Jolla, Calif.) and then probed using QUICKHYB™ hybridization solution (Stratagene, La Jolla, Calif.) using manufacturer&#39;s recommendations for stringent conditions.  
     [0279] To detect human PAZ/PIWI domain-containing protein, a human PAZ/PIWI domain-containing protein specific probe was prepared by PCR using the forward primer AAATTTGTCTCTCGGGTGAGTTG (SEQ ID NO: 5) and the reverse primer TTAGTGCTGATTGGCTTGTCTAATTC (SEQ ID NO: 6). To normalize for variations in loading and transfer efficiency membranes were stripped and probed for human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) RNA (Clontech, Palo Alto, Calif.).  
     [0280] Hybridized membranes were visualized and quantitated using a PHOSPHORIMAGER™ and IMAGEQUANT™ Software V3.3 (Molecular Dynamics, Sunnyvale, Calif.). Data was normalized to GAPDH levels in untreated controls.  
     Example 15  
     [0281] Antisense Inhibition of Human PAZ/PIWI Domain-Containing Protein Expression by Chimeric Phosphorothioate Oligonucleotides Having 2′-MOE Wings and a Deoxy Gap  
     [0282] In accordance with the present invention, a series of oligonucleotides were designed to target different regions of the human PAZ/PIWI domain-containing protein RNA, using published sequences (GenBank accession number NM — 024852.1, incorporated herein as SEQ ID NO: 4, GenBank accession number BF980145.1, the complement of which is incorporated herein as SEQ ID NO: 11, GenBank accession number AI870324.1, the complement of which is incorporated herein as SEQ ID NO: 12, residues 2461000-2587000 of GenBank accession number NT — 004568.7, the complement of which is incorporated herein as SEQ ID NO: 13, and GenBank accession number AK027796.1, incorporated herein as SEQ ID NO: 14). The oligonucleotides are shown in Table 1. “Target site” indicates the first (5′-most) nucleotide number on the particular target sequence to which the oligonucleotide binds. All compounds in Table 1 are chimeric oligonucleotides (“gapmers”) 20 nucleotides in length, composed of a central “gap” region consisting of ten 2′-deoxynucleotides, which is flanked on both sides (5′ and 3′ directions) by five-nucleotide “wings”. The wings are composed of 2′-methoxyethyl (2′-MOE)nucleotides. The internucleoside (backbone) linkages are phosphorothioate (P═S) throughout the oligonucleotide. All cytidine residues are 5-methylcytidines. The compounds were analyzed for their effect on human PAZ/PIWI domain-containing protein mRNA levels by quantitative real-time PCR as described in other examples herein. Data are averages from two experiments in which A549 were treated with the antisense oligonucleotides of the present invention. The positive control for each datapoint is identified in the table by sequence ID number. If present, “N.D.” indicates “no data”.  
               TABLE 1                          Inhibition of human PAZ/PIWI domain-containing protein mRNA levels by chimeric       phosphorothioate oligonucleotides having 2′-MOE wings and a deoxy gap                                                     TARGET                   CONTROL               SEQ ID   TARGET       %   SEQ ID   SEQ ID       ISIS #   REGION   NO   SITE   SEQUENCE   INHIB   NO   NO                                                     241284   5′UTR   4   52   agaacggagcccgccactgg   80   15   1       241285   Start   4   92   ccgatttccattcatggagc   69   16   1           Codon       241286   Coding   4   196   cttgaaaacagttagccagc   93   17   1       241287   Coding   4   230   tcatagaggtagacatcaat   53   18   1       241288   Coding   4   285   gtcaaccacctccctgttca   83   19   1       241289   Coding   4   290   attgagtcaaccacctccct   91   20   1       241290   Coding   4   307   ctttaaaatgctgaaccatt   88   21   1       241291   Coding   4   344   ccatcataaactggtctacg   88   22   1       241292   Coding   4   367   tggcggtgtaaagacttctt   84   23   1       241293   Coding   4   374   agtggattggcggtgtaaag   77   24   1       241294   Coding   4   391   ctgtagttgccacaggaagt   87   25   1       241295   Coding   4   403   ctaaatctacccctgtagtt   52   26   1       241296   Coding   4   508   gtcctgtcagtacttcatgc   99   27   1       241297   Coding   4   535   ctaattccagtggctcaggc   98   28   1       241298   Coding   4   574   catcaacggcatggacaggg   86   29   1       241299   Coding   4   603   tttcatggagggcagatgtc   78   30   1       241300   Coding   4   612   aggtgtgtatttcatggagg   75   31   1       241301   Coding   4   641   tctggagcggagaaaaatga   51   32   1       241302   Coding   4   703   gaacagactgatggaatcca   89   33   1       241303   Coding   4   911   ctcattgttccacaatgagt   57   34   1       241304   Coding   4   946   gcctccttgttacattacaa   77   35   1       241305   Coding   4   1002   tctctccacagtttggccgt   67   36   1       241306   Coding   4   1037   agagtatacttttctctgaa   68   37   1       241307   Coding   4   1052   gggtacttcagctgaagagt   63   38   1       241308   Coding   4   1081   cctgcccgacttgcagacag   74   39   1       241309   Coding   4   1214   tcttgtctatctggtgcaga   57   40   1       241310   Coding   4   1246   aatttgcacttcttaccaat   64   41   1       241311   Coding   4   1258   gatctgtttcataatttgca   53   42   1       241312   Coding   4   1277   tgaaactcctgaacaaatgg   61   43   1       241313   Coding   4   1285   ctttaaattgaaactcctga   60   44   1       241314   Coding   4   1293   atcccgaactttaaattgaa   59   45   1       241315   Coding   4   1300   ccatttcatcccgaacttta   61   46   1       241316   Coding   4   1307   acatgagccatttcatcccg   76   47   1       241317   Coding   4   1324   gaagtacgcgtccagttaca   74   48   1       241318   Coding   4   1363   ctgtccgattccgtcctcca   52   49   1       241319   Coding   4   1388   catactccatggctcggtgt   69   50   1       241320   Coding   4   1425   ttcaactcctgtgtggaatt   68   51   1       241321   Coding   4   1496   gtgaaacccttcaatatttc   58   52   1       241322   Coding   4   1626   gccagaatatgtgttcttga   69   53   1       241323   Coding   4   1644   gacgataataagctgtaggc   59   54   1       241324   Coding   4   1741   ttacattcttgacttgaaca   69   55   1       241325   Coding   4   1792   taacatttatctttaggcac   63   56   1       241326   Coding   4   1815   aatattattgatccctccga   49   57   1       241327   Coding   4   1888   gtggatgagtgacatcggct   54   58   1       241328   Coding   4   2031   aagttcccggaccatggagg   69   59   1       241329   Coding   4   2104   cctctgaaacaccatcccga   57   60   1       241330   Coding   4   2136   tagttcataatataatacct   59   61   1       241331   Coding   4   2169   ctccaaactgatgcaggctt   12   62   1       241332   Coding   4   2202   tacaatgtaggttattccag   66   63   1       241333   Coding   4   2237   gcacaaaataatcgagtgtg   66   64   1       241334   Coding   4   2259   tccaaccctttctgtcctat   55   65   1       241335   Coding   4   2276   gggatattgccacttcttcc   0   66   1       241336   Coding   4   2310   gtgtgtaatgtctgtatcaa   65   67   1       241337   Coding   4   2512   ctaccaggtgagcataatac   56   68   1       241338   Coding   4   2617   ccttggcaagagcttgtgga   62   69   1       241339   Coding   4   2650   ttgtgcgtaaggtatcttgg   64   70   1       241340   Stop   4   2673   ttggactatttaagcgaagt   58   71   1           Codon       241341   3′UTR   4   2697   agtacttcctctcagagaat   71   72   1       241342   3′UTR   4   2758   ggaggtgtccttactcaatt   66   73   1       241343   3′UTR   4   2805   taaggatcagaccttggccc   55   74   1       241344   3′UTR   4   2851   gatgctgtgttccttgatga   68   75   1       241345   3′UTR   4   2893   agaccgcacaaaaagcagtt   64   76   1       241346   3′UTR   4   2990   caaagatagttgtgctgcca   71   77   1       241347   exon:   11   340   aggtctctttcatcgatatt   41   78   1           exon           junction       241348   exon   11   615   gctttcgttctaacaggagg   75   79   1       241349   exon   11   645   tggtgaataaaatgacaatc   78   80   1       241350   intron   12   519   cagaaatccaccacccaata   73   81   1       241351   intron   13   6210   ataccacgttctgatttccc   80   82   1       241352   intron:   13   36470   aaccacctccctaaagaagg   79   83   1           exon           junction       241353   intron:   13   52136   aggtctctttctggaaaaca   89   84   1           exon           junction       241354   intron   13   57925   aagcatagaaactttcagtt   18   85   1       241355   exon:   13   83268   gagactttacccgtcctcca   76   86   1           intron           junction       241356   intron   13   92802   accagtcagactctctgtgt   69   87   1       241357   intron   13   97081   gaactcctgacctcaggtga   87   88   1       241358   exon:   13   113064   gtaggcttacctgtattcca   37   89   1           intron           junction       241359   5′UTR   14   72   cggcacaggactggagccgg   26   90   1       241360   5′UTR   14   123   tgagcaaccgcactccgaaa   91   91   1       241361   5′UTR   14   129   ttcccctgagcaaccgcact   77   92   1                  
 
     [0283] As shown in Table 1, SEQ ID NOs 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 59, 60, 61, 62, 63, 64, 65, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 79, 80, 81, 82, 83, 84, 86, 87, 88, 91 and 92 demonstrated at least 50% inhibition of human PAZ/PIWI domain-containing protein expression in this assay and are therefore preferred. The target sites to which these preferred sequences are complementary are herein referred to as “preferred target regions” and are therefore preferred sites for targeting by compounds of the present invention. These preferred target regions are shown in Table 2. The sequences represent the reverse complement of the preferred antisense compounds shown in Table 1. “Target site” indicates the first (5′-most) nucleotide number of the corresponding target nucleic acid. Also shown in Table 2 is the species in which each of the preferred target regions was found.  
               TABLE 2                          Sequence and position of preferred target regions identified       in PAZ/PIWI domain-containing protein.                                             TARGET           REV COMP               SITE   SEQ ID   TARGET       OF SEQ       SEQ ID       ID   NO   SITE   SEQUENCE   ID   ACTIVE IN   NO                                                 157800   4   52   ccagtggcgggctccgttct   15     H. sapiens     93       157801   4   92   gctccatgaatggaaatcgg   16     H. sapiens     94       157802   4   196   gctggctaactgttttcaag   17     H. sapiens     95       157803   4   230   attgatgtctacctctatga   18     H. sapiens     96       157804   4   285   tgaacagggaggtggttgac   19     H. sapiens     97       157805   4   290   agggaggtggttgactcaat   20     H. sapiens     98       157806   4   307   aatggttcagcattttaaag   21     H. sapiens     99       157807   4   344   cgtagaccagtttatgatgg   22     H. sapiens     100       157808   4   367   aagaagtctttacaccgcca   23     H. sapiens     101       157809   4   374   ctttacaccgccaatccact   24     H. sapiens     102       157810   4   391   acttcctgtggcaactacag   25     H. sapiens     103       157811   4   403   aactacaggggtagatttag   26     H. sapiens     104       157812   4   508   gcatgaagtactgacaggac   27     H. sapiens     105       157813   4   535   gcctgagccactggaattag   28     H. sapiens     106       157814   4   574   ccctgtccatgccgttgatg   29     H. sapiens     107       157815   4   603   gacatctgccctccatgaaa   30     H. sapiens     108       157816   4   612   cctccatgaaatacacacct   31     H. sapiens     109       157817   4   641   tcatttttctccgctccaga   32     H. sapiens     110       157818   4   703   tggattccatcagtctgttc   33     H. sapiens     111       157819   4   911   actcattgtggaacaatgag   34     H. sapiens     112       157820   4   946   ttgtaatgtaacaaggaggc   35     H. sapiens     113       157821   4   1002   acggccaaactgtggagaga   36     H. sapiens     114       157822   4   1037   ttcagagaaaagtatactct   37     H. sapiens     115       157823   4   1052   actcttcagctgaagtaccc   38     H. sapiens     116       157824   4   1081   ctgtctgcaagtcgggcagg   39     H. sapiens     117       157825   4   1214   tctgcaccagatagacaaga   40     H. sapiens     118       157826   4   1246   attggtaagaagtgcaaatt   41     H. sapiens     119       157827   4   1258   tgcaaattatgaaacagatc   42     H. sapiens     120       157828   4   1277   ccatttgttcaggagtttca   43     H. sapiens     121       157829   4   1285   tcaggagtttcaatttaaag   44     H. sapiens     122       157830   4   1293   ttcaatttaaagttcgggat   45     H. sapiens     123       157831   4   1300   taaagttcgggatgaaatgg   46     H. sapiens     124       157832   4   1307   cgggatgaaatggctcatgt   47     H. sapiens     125       157833   4   1324   tgtaactggacgcgtacttc   48     H. sapiens     126       157834   4   1363   tggaggacggaatcggacag   49     H. sapiens     127       157835   4   1388   acaccgagccatggagtatg   50     H. sapiens     128       157836   4   1425   aattccacacaggagttgaa   51     H. sapiens     129       157837   4   1496   gaaatattgaagggtttcac   52     H. sapiens     130       157838   4   1626   tcaagaacacatattctggc   53     H. sapiens     131       157839   4   1644   gcctacagcttattatcgtc   54     H. sapiens     132       157840   4   1741   tgttcaagtcaagaatgtaa   55     H. sapiens     133       157841   4   1792   gtgcctaaagataaatgtta   56     H. sapiens     134       157843   4   1888   agccgatgtcactcatccac   58     H. sapiens     135       157844   4   2031   cctccatggtccgggaactt   59     H. sapiens     136       157845   4   2104   tcgggatggtgtttcagagg   60     H. sapiens     137       157846   4   2136   aggtattatattatgaacta   61     H. sapiens     138       157847   4   2169   aagcctgcatcagtttggag   62     H. sapiens     139       157848   4   2202   ctggaataacctacattgta   63     H. sapiens     140       157849   4   2237   cacactcgattattttgtgc   64     H. sapiens     141       157850   4   2259   ataggacagaaagggttgga   65     H. sapiens     142       157852   4   2310   ttgatacagacattacacac   67     H. sapiens     143       157853   4   2512   gtattatgctcacctggtag   68     H. sapiens     144       157854   4   2617   tccacaagctcttgccaagg   69     H. sapiens     145       157855   4   2650   ccaagataccttacgcacaa   70     H. sapiens     146       157856   4   2673   acttcgcttaaatagtccaa   71     H. sapiens     147       157857   4   2697   attctctgagaggaagtact   72     H. sapiens     148       157858   4   2758   aattgagtaaggacacctcc   73     H. sapiens     149       157859   4   2805   gggccaaggtctgatcctta   74     H. sapiens     150       157860   4   2851   tcatcaaggaacacagcatc   75     H. sapiens     151       157861   4   2893   aactgctttttgtgcggtct   76     H. sapiens     152       157862   4   2990   tggcagcacaactatctttg   77     H. sapiens     153       157864   11   615   cctcctgttagaacgaaagc   79     H. sapiens     154       157865   11   645   gattgtcattttattcacca   80     H. sapiens     155       157866   12   519   tattgggtggtggatttctg   81     H. sapiens     156       157867   13   6210   gggaaatcagaacgtggtat   82     H. sapiens     157       157868   13   36470   ccttctttagggaggtggtt   83     H. sapiens     158       157869   13   52136   tgttttccagaaagagacct   84     H. sapiens     159       157871   13   83268   tggaggacgggtaaagtctc   86     H. sapiens     160       157872   13   92802   acacagagagtctgactggt   87     H. sapiens     161       157873   13   97081   tcacctgaggtcaggagttc   88     H. sapiens     162       157876   14   123   tttcggagtgcggttgctca   91     H. sapiens     163       157877   14   129   agtgcggttgctcaggggaa   92     H. sapiens     164                  
 
     [0284] As these “preferred target regions” have been found by experimentation to be open to, and accessible for, hybridization with the antisense compounds of the present invention, one of skill in the art will recognize or be able to ascertain, using no more than routine experimentation, further embodiments of the invention that encompass other compounds that specifically hybridize to these sites and consequently inhibit the expression of PAZ/PIWI domain-containing protein.  
     [0285] In one embodiment, the “preferred target region” may be employed in screening candidate antisense compounds. “Candidate antisense compounds” are those that inhibit the expression of a nucleic acid molecule encoding PAZ/PIWI domain-containing protein and which comprise at least an 8-nucleobase portion which is complementary to a preferred target region. The method comprises the steps of contacting a preferred target region of a nucleic acid molecule encoding PAZ/PIWI domain-containing protein with one or more candidate antisense compounds, and selecting for one or more candidate antisense compounds which inhibit the expression of a nucleic acid molecule encoding PAZ/PIWI domain-containing protein. Once it is shown that the candidate antisense compound or compounds are capable of inhibiting the expression of a nucleic acid molecule encoding PAZ/PIWI domain-containing protein, the candidate antisense compound may be employed as an antisense compound in accordance with the present invention.  
     [0286] According to the present invention, antisense compounds include ribozymes, external guide sequence (EGS) oligonucleotides (oligozymes), and other short catalytic RNAs or catalytic oligonucleotides which hybridize to the target nucleic acid and modulate its expression.  
     Example 16  
     [0287] Western Blot Analysis of PAZ/PIWI Domain-Containing Protein Protein Levels  
     [0288] Western blot analysis (immunoblot analysis) is carried out using standard methods. Cells are harvested 16-20 h after oligonucleotide treatment, washed once with PBS, suspended in Laemmli buffer (100 ul/well), boiled for 5 minutes and loaded on a 16% SDS-PAGE gel. Gels are run for 1.5 hours at 150 V, and transferred to membrane for western blotting. Appropriate primary antibody directed to PAZ/PIWI domain-containing protein is used, with a radiolabeled or fluorescently labeled secondary antibody directed against the primary antibody species. Bands are visualized using a PHOSPHORIMAGER™ (Molecular Dynamics, Sunnyvale Calif.).  
    
     
       
         1 
         
           
             164  
           
           
             1  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            1 

tccgtcatcg ctcctcaggg                                                 20 

 
           
             2  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            2 

gtgcgcgcga gcccgaaatc                                                 20 

 
           
             3  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            3 

atgcattctg cccccaagga                                                 20 

 
           
             4  
             3050  
             DNA  
             H. sapiens  
             
 
             
               CDS  
               (101)...(2683)  
             
           
            4 

tgagtgcccg tcgcgtcgcg ccgcgtcgcc ccccgggccg cctccttgcc gccagtggcg     60 

ggctccgttc tccctcgaag cactcccccc agctccatga  atg gaa atc ggc tcc     115 
                                             Met Glu Ile Gly Ser 
                                               1               5 

gca gga ccc gct ggg gcc cag ccc cta ctc atg gtg ccc aga aga cct      163 
Ala Gly Pro Ala Gly Ala Gln Pro Leu Leu Met Val Pro Arg Arg Pro 
                 10                  15                  20 

ggc tat ggc gcc atg ggc aaa ccc att aaa ctg ctg gct aac tgt ttt      211 
Gly Tyr Gly Ala Met Gly Lys Pro Ile Lys Leu Leu Ala Asn Cys Phe 
             25                  30                  35 

caa gtt gaa atc cca aag att gat gtc tac ctc tat gag gta gat att      259 
Gln Val Glu Ile Pro Lys Ile Asp Val Tyr Leu Tyr Glu Val Asp Ile 
         40                  45                  50 

aaa cca gac aag tgt cct agg aga gtg aac agg gag gtg gtt gac tca      307 
Lys Pro Asp Lys Cys Pro Arg Arg Val Asn Arg Glu Val Val Asp Ser 
     55                  60                  65 

atg gtt cag cat ttt aaa gta act ata ttt gga gac cgt aga cca gtt      355 
Met Val Gln His Phe Lys Val Thr Ile Phe Gly Asp Arg Arg Pro Val 
 70                  75                  80                  85 

tat gat gga aaa aga agt ctt tac acc gcc aat cca ctt cct gtg gca      403 
Tyr Asp Gly Lys Arg Ser Leu Tyr Thr Ala Asn Pro Leu Pro Val Ala 
                 90                  95                 100 

act aca ggg gta gat tta gac gtt act tta cct ggg gaa ggt gga aaa      451 
Thr Thr Gly Val Asp Leu Asp Val Thr Leu Pro Gly Glu Gly Gly Lys 
            105                 110                 115 

gat cga cct ttc aag gtg tca atc aaa ttt gtc tct cgg gtg agt tgg      499 
Asp Arg Pro Phe Lys Val Ser Ile Lys Phe Val Ser Arg Val Ser Trp 
        120                 125                 130 

cac cta ctg cat gaa gta ctg aca gga cgg act ttg cct gag cca ctg      547 
His Leu Leu His Glu Val Leu Thr Gly Arg Thr Leu Pro Glu Pro Leu 
    135                 140                 145 

gaa tta gac aag cca atc agc act aac cct gtc cat gcc gtt gat gtg      595 
Glu Leu Asp Lys Pro Ile Ser Thr Asn Pro Val His Ala Val Asp Val 
150                 155                 160                 165 

gtg cta cga cat ctg ccc tcc atg aaa tac aca cct gtg ggg cgt tca      643 
Val Leu Arg His Leu Pro Ser Met Lys Tyr Thr Pro Val Gly Arg Ser 
                170                 175                 180 

ttt ttc tcc gct cca gaa gga tat gac cac cct ctg gga ggg ggc agg      691 
Phe Phe Ser Ala Pro Glu Gly Tyr Asp His Pro Leu Gly Gly Gly Arg 
            185                 190                 195 

gaa gtg tgg ttt gga ttc cat cag tct gtt cgg cct gcc atg tgg aaa      739 
Glu Val Trp Phe Gly Phe His Gln Ser Val Arg Pro Ala Met Trp Lys 
        200                 205                 210 

atg atg ctt aat atc gat gtt tct gcc act gcc ttc tac aaa gca caa      787 
Met Met Leu Asn Ile Asp Val Ser Ala Thr Ala Phe Tyr Lys Ala Gln 
    215                 220                 225 

cct gta att cag ttc atg tgt gaa gtt ctt gat att cat aat att gat      835 
Pro Val Ile Gln Phe Met Cys Glu Val Leu Asp Ile His Asn Ile Asp 
230                 235                 240                 245 

gag caa cca aga cct ctg act gat tct cat cgg gta aaa ttc acc aaa      883 
Glu Gln Pro Arg Pro Leu Thr Asp Ser His Arg Val Lys Phe Thr Lys 
                250                 255                 260 

gag ata aaa ggt ttg aag gtt gaa gtg act cat tgt gga aca atg aga      931 
Glu Ile Lys Gly Leu Lys Val Glu Val Thr His Cys Gly Thr Met Arg 
            265                 270                 275 

cgg aaa tac cgt gtt tgt aat gta aca agg agg cct gcc agt cat caa      979 
Arg Lys Tyr Arg Val Cys Asn Val Thr Arg Arg Pro Ala Ser His Gln 
        280                 285                 290 

acc ttt cct tta cag tta gaa aac ggc caa act gtg gag aga aca gta     1027 
Thr Phe Pro Leu Gln Leu Glu Asn Gly Gln Thr Val Glu Arg Thr Val 
    295                 300                 305 

gcg cag tat ttc aga gaa aag tat act ctt cag ctg aag tac ccg cac     1075 
Ala Gln Tyr Phe Arg Glu Lys Tyr Thr Leu Gln Leu Lys Tyr Pro His 
310                 315                 320                 325 

ctt ccc tgt ctg caa gtc ggg cag gaa cag aaa cac acc tac ctg cca     1123 
Leu Pro Cys Leu Gln Val Gly Gln Glu Gln Lys His Thr Tyr Leu Pro 
                330                 335                 340 

cta gaa gtc tgt aat att gtg gca ggg caa cga tgt atc aag aag cta     1171 
Leu Glu Val Cys Asn Ile Val Ala Gly Gln Arg Cys Ile Lys Lys Leu 
            345                 350                 355 

aca gac aat cag act tcc act atg atc aag gca aca gca aga tct gca     1219 
Thr Asp Asn Gln Thr Ser Thr Met Ile Lys Ala Thr Ala Arg Ser Ala 
        360                 365                 370 

cca gat aga caa gag gaa att agc aga ttg gta aga agt gca aat tat     1267 
Pro Asp Arg Gln Glu Glu Ile Ser Arg Leu Val Arg Ser Ala Asn Tyr 
    375                 380                 385 

gaa aca gat cca ttt gtt cag gag ttt caa ttt aaa gtt cgg gat gaa     1315 
Glu Thr Asp Pro Phe Val Gln Glu Phe Gln Phe Lys Val Arg Asp Glu 
390                 395                 400                 405 

atg gct cat gta act gga cgc gta ctt cca gca cct atg ctc cag tat     1363 
Met Ala His Val Thr Gly Arg Val Leu Pro Ala Pro Met Leu Gln Tyr 
                410                 415                 420 

gga gga cgg aat cgg aca gta gca aca ccg agc cat gga gta tgg gac     1411 
Gly Gly Arg Asn Arg Thr Val Ala Thr Pro Ser His Gly Val Trp Asp 
            425                 430                 435 

atg cga ggg aaa caa ttc cac aca gga gtt gaa atc aaa atg tgg gct     1459 
Met Arg Gly Lys Gln Phe His Thr Gly Val Glu Ile Lys Met Trp Ala 
        440                 445                 450 

atc gct tgt ttt gcc aca cag agg cag tgc aga gaa gaa ata ttg aag     1507 
Ile Ala Cys Phe Ala Thr Gln Arg Gln Cys Arg Glu Glu Ile Leu Lys 
    455                 460                 465 

ggt ttc aca gac cag ctg cgt aag att tct aag gat gca ggg atg ccc     1555 
Gly Phe Thr Asp Gln Leu Arg Lys Ile Ser Lys Asp Ala Gly Met Pro 
470                 475                 480                 485 

atc cag ggc cag cca tgc ttc tgc aaa tat gca cag ggg gca gac agc     1603 
Ile Gln Gly Gln Pro Cys Phe Cys Lys Tyr Ala Gln Gly Ala Asp Ser 
                490                 495                 500 

gta gag ccc atg ttc cgg cat ctc aag aac aca tat tct ggc cta cag     1651 
Val Glu Pro Met Phe Arg His Leu Lys Asn Thr Tyr Ser Gly Leu Gln 
            505                 510                 515 

ctt att atc gtc atc ctg ccg ggg aag aca cca gtg tat gcg gaa gtg     1699 
Leu Ile Ile Val Ile Leu Pro Gly Lys Thr Pro Val Tyr Ala Glu Val 
        520                 525                 530 

aaa cgt gta gga gac aca ctt ttg ggt atg gct aca caa tgt gtt caa     1747 
Lys Arg Val Gly Asp Thr Leu Leu Gly Met Ala Thr Gln Cys Val Gln 
    535                 540                 545 

gtc aag aat gta ata aaa aca tct cct caa act ctg tca aac ttg tgc     1795 
Val Lys Asn Val Ile Lys Thr Ser Pro Gln Thr Leu Ser Asn Leu Cys 
550                 555                 560                 565 

cta aag ata aat gtt aaa ctc gga ggg atc aat aat att ctt gta cct     1843 
Leu Lys Ile Asn Val Lys Leu Gly Gly Ile Asn Asn Ile Leu Val Pro 
                570                 575                 580 

cat caa aga cct tct gtg ttc cag caa cca gtg atc ttt ttg gga gcc     1891 
His Gln Arg Pro Ser Val Phe Gln Gln Pro Val Ile Phe Leu Gly Ala 
            585                 590                 595 

gat gtc act cat cca cct gct ggt gat gga aag aag cct tct att gct     1939 
Asp Val Thr His Pro Pro Ala Gly Asp Gly Lys Lys Pro Ser Ile Ala 
        600                 605                 610 

gct gtt gta ggt agt atg gat gca cac cca agc aga tac tgt gcc aca     1987 
Ala Val Val Gly Ser Met Asp Ala His Pro Ser Arg Tyr Cys Ala Thr 
    615                 620                 625 

gta aga gtt cag aga ccc cga cag gag atc atc cag gac ttg gcc tcc     2035 
Val Arg Val Gln Arg Pro Arg Gln Glu Ile Ile Gln Asp Leu Ala Ser 
630                 635                 640                 645 

atg gtc cgg gaa ctt ctt att caa ttt tat aag tca act cgg ttc aag     2083 
Met Val Arg Glu Leu Leu Ile Gln Phe Tyr Lys Ser Thr Arg Phe Lys 
                650                 655                 660 

cct act cgt atc atc ttt tat cgg gat ggt gtt tca gag ggg cag ttt     2131 
Pro Thr Arg Ile Ile Phe Tyr Arg Asp Gly Val Ser Glu Gly Gln Phe 
            665                 670                 675 

agg cag gta tta tat tat gaa cta cta gca att cga gaa gcc tgc atc     2179 
Arg Gln Val Leu Tyr Tyr Glu Leu Leu Ala Ile Arg Glu Ala Cys Ile 
        680                 685                 690 

agt ttg gag aaa gac tat caa cct gga ata acc tac att gta gtt cag     2227 
Ser Leu Glu Lys Asp Tyr Gln Pro Gly Ile Thr Tyr Ile Val Val Gln 
    695                 700                 705 

aag aga cat cac act cga tta ttt tgt gct gat agg aca gaa agg gtt     2275 
Lys Arg His His Thr Arg Leu Phe Cys Ala Asp Arg Thr Glu Arg Val 
710                 715                 720                 725 

gga aga agt ggc aat atc cca gct gga aca aca gtt gat aca gac att     2323 
Gly Arg Ser Gly Asn Ile Pro Ala Gly Thr Thr Val Asp Thr Asp Ile 
                730                 735                 740 

aca cac cca tat gag ttc gat ttt tac ctc tgt agc cat gct gga ata     2371 
Thr His Pro Tyr Glu Phe Asp Phe Tyr Leu Cys Ser His Ala Gly Ile 
            745                 750                 755 

cag ggt acc agt cgt cct tca cac tat cat gtt tta tgg gat gat aac     2419 
Gln Gly Thr Ser Arg Pro Ser His Tyr His Val Leu Trp Asp Asp Asn 
        760                 765                 770 

tgc ttt act gca gat gaa ctt cag ctg cta act tac cag ctc tgc cac     2467 
Cys Phe Thr Ala Asp Glu Leu Gln Leu Leu Thr Tyr Gln Leu Cys His 
    775                 780                 785 

act tac gta cgc tgt aca cga tct gtt tct ata cct gca cca gcg tat     2515 
Thr Tyr Val Arg Cys Thr Arg Ser Val Ser Ile Pro Ala Pro Ala Tyr 
790                 795                 800                 805 

tat gct cac ctg gta gca ttt aga gcc aga tat cat ctt gtg gac aaa     2563 
Tyr Ala His Leu Val Ala Phe Arg Ala Arg Tyr His Leu Val Asp Lys 
                810                 815                 820 

gaa cat gac agt gct gaa gga agt cac gtt tca gga caa agc aat ggg     2611 
Glu His Asp Ser Ala Glu Gly Ser His Val Ser Gly Gln Ser Asn Gly 
            825                 830                 835 

cga gat cca caa gct ctt gcc aag gct gta cag att cac caa gat acc     2659 
Arg Asp Pro Gln Ala Leu Ala Lys Ala Val Gln Ile His Gln Asp Thr 
        840                 845                 850 

tta cgc aca atg tac ttc gct taa atagtccaag tatattctct gagaggaagt    2713 
Leu Arg Thr Met Tyr Phe Ala 
    855                 860 

actgaaagat gaattgacat acaacgtatg tttccagtga agtcaattga gtaaggacac   2773 

ctccagccat acagaaacca acactgtgtg ggggccaagg tctgatcctt atgttaacac   2833 

aaggaagatt gtttacttca tcaaggaaca cagcatcatt atgcaatatg aaaccagcca   2893 

actgcttttt gtgcggtctc ctataggaag tatcgcaatt gtcttgtttt catttcttgt   2953 

agtctaaccc ttttaatgcc tttacctcaa gttgcttggc agcacaacta tctttgcaaa   3013 

aaaaagtaaa gaaaaagtaa atgatggttt aaaaaat                            3050 

 
           
             5  
             23  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            5 

aaatttgtct ctcgggtgag ttg                                             23 

 
           
             6  
             26  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            6 

ttagtgctga ttggcttgtc taattc                                          26 

 
           
             7  
             25  
             DNA  
             Artificial Sequence  
             
               PCR Probe  
             
           
            7 

agtactgaca ggacggactt tgcct                                           25 

 
           
             8  
             19  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            8 

gaaggtgaag gtcggagtc                                                  19 

 
           
             9  
             20  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            9 

gaagatggtg atgggatttc                                                 20 

 
           
             10  
             20  
             DNA  
             Artificial Sequence  
             
               PCR Probe  
             
           
            10 

caagcttccc gttctcagcc                                                 20 

 
           
             11  
             676  
             DNA  
             H. sapiens  
             
 
           
            11 

gggtagattt agacgttact ttacctgggg aaggtggaaa agatcgacct gtcaaggtgt    60 

caatcaaatt tgtctctcgg gtgagttggc acctactgca tgaagtactg acaggacgga   120 

ccttgcctga gccactggaa ttagacaagc caatcagcac taaccctgtc catgccgttg   180 

atgtggtgct acgacatctg ccctccatga aatacacacc tgtggggcgt tcatttttct   240 

ccagctccag aaggatatga ccaccctctg ggagggggca gggaagtgtg gtttggattc   300 

catcagtctg ttcggcctgc catgtggaaa atgatgctta atatcgatga aagagacctc   360 

tggcagcagt gtggagaata gatagaggag aaaaaactaa tctgagaagc cagttaggag   420 

gcttttcaat cactagttca ggtttcagtc tacatgttac ttccttgaga agcagtgttt   480 

gacacccttc tcccccaatc cagccatccc ccaagtctga gttaggtatt tctcttctgt   540 

attcccatag cacagtgtaa ttcccctata atagcatgta tcaccttgaa ttatgggtgt   600 

ttattgttct gtctcctcct gttagaacga aagctccatg aagggattgt cattttattc   660 

accagtgtac cctcta                                                   676 

 
           
             12  
             574  
             DNA  
             H. sapiens  
             
               unsure  
               356  
               unknown  
             
           
            12 

gacaagtgtc ctaggagagt gaacaggaag gtggttgact caatggttca gcattttaaa    60 

gtaactatat ttggagaccg tagaccagtt tatgatggaa aaagaagtct ttacaccgcc   120 

aatccacttc ctgtggcaac tacaggggta gatttagacg ttactttacc tggggaaggt   180 

ggaaaagatc gacctttcaa ggtgtcaatc aaatttgtct ctcgggtgag ttggcaccta   240 

ctgcatgaag tactgacagg acggaccttg cctgagccac tggaattaga caagccaatc   300 

agcactaacc ctgtccatgc cgttgatgtg gtgctacgac atctgccctc catganatac   360 

acacctgtgg ggcgttcatt tttctccgct ccagaaggat atgaccaccc tctgggaggg   420 

ggcagggaag tgtggtttgg attccatcag tctgttcggc ctgccatgtg gaaaatgatg   480 

cttaatatcg atggtaaggg aactaaagcc atattctgta ttgggtggtg gatttctgta   540 

tgatgtgtgt acataaattt tatatataat tata                               574 

 
           
             13  
             126001  
             DNA  
             H. sapiens  
             
 
           
            13 

aggagtttgg gttttcaagt gtgacgaggc gctattaaag agttttaaac atggaaatta     60 

ctcgatctga tgtttgtgta gtgtcctgtt tgttagtcat cttttccaaa ctataataca    120 

tttttttttt cctaaaaatg gtcgttaaag cagcctagga cttaggtcaa ttgcggtggt    180 

cacttgaccg cctgtgagga ggcggcgcgt ggggtggatc ggactgggcg tggcgggggc    240 

tcaggaagga gggtggccct accccagcgg gctcggctcg gggcctccgc ggcagttcgg    300 

ggtccttcac ccgccggctc caggtaggct actcctcagg taagccccgc cgccagccgc    360 

gacgtcgtcg cagacaggca ccgcccccac tcgtgcggcg cgagtagtcc tgcccctccg    420 

cgttgtctcc ggccggcacg gcccggcggg gtacggccga gcccgccgca tgtggcccgg    480 

ctcccggaca cctccccggc gtcctccgcg ccggccgctc ctgccccgac gtcgctccgg    540 

cacggctcgg ggcccagagg cgaggcgagg acgccgggca agccaggcag cggaactgac    600 

gccggcgagc ttccggggcg gccccgggca ggtcggcggc ggcggcccgc agtcgtggag    660 

gagcggtggg agcgtcggcg gccgcgggcg atgcaacttc cggacgggac tcccctctgt    720 

ccgcgcctca catctcccct tcctctcgcc tagtcctgtg ccgttttccg tccgcgactc    780 

ttccggccca gagctttcgg agtgcggttg ctcaggggaa gccgtcgccg cccccgcctc    840 

ggggccgagt gagagtgccc gtcgcgtcgc gccgcgtcgc cccccgggcc gcctccttgc    900 

cgccagtggc gggctccgtt ctccctcgaa gcactccccc cagctccatg aatggaaatc    960 

ggctccgcag gtgagtcaga gtagctgggc caggtagggg atgtcaccca gctactgtcc   1020 

tctgagcatc cctgctcctc ccgcccggcc caggtgcgcg aggtgagcgt cgggcgggca   1080 

tcgctcggtc tcccgcccct cgccctgctc ctccgcgacc tccccgcagc ccagccccag   1140 

ttccccgggg gcccctgagt cggcgaaact gcgaggcggg gaaacgcttg gaggatttaa   1200 

gtttggggtt atctaggcgg cattactctt tgctggagta cccttcttct agactttaga   1260 

atggtttgcc attgtctagt tggagtgcgt gtcctttagc caggttgtgt gttccgtaga   1320 

ggctgggcag ccagccagct cccttaccta cctcttagga tagttgtgaa gataggctga   1380 

gataacggat aacttcagat taagttcgaa ggaggtgttg gtgcaacgtt aaattcaaca   1440 

tggcattgct cctaccctcg agttcttttc tgttgtttgt ggcagcatgg tagatagttt   1500 

ctgaggagct tggaaatgtc atagcagcct ggatccctgc ttatacgagg aggtggttct   1560 

taaaattgct gacagtatat tttttttcat tctctattcc ttagagaagt agttgtcata   1620 

ttcctggaaa tttggaattt aagaaaactg ctttatctct gggggcaaga gcagcagttt   1680 

tgcagtctta agagaaaatt gcaacatgga tagtacttgt ccttaaaaaa ggaaaagtat   1740 

tgtttatggt tctaaagtaa ttaattcagg gacagaaagg tgttgcataa cggtttgcct   1800 

aacaaatgat catgcttggc ttattaaatt tgaaagtatg cttcagacga tcacaagttc   1860 

gtaaattaat tttcaaaata tttgcggggc tgtcttgtta ctaatggtgt tacaagttcc   1920 

tgaattccat atctcttttt gccaatttga tataagaaaa acttacgtaa aagaaaccag   1980 

tgacataacg atagctaaga actttgttga atagattacg tgtcaaatgg ttgcaaaaaa   2040 

gcactcaaac tggggagatg agatggggag agagttacaa attttttttt ttttttttta   2100 

caaattttgt tacatggaag tttctctaat caatttagac catatctctt tttcctgctc   2160 

cattgtttcg ctttccccca tatcgtctta aaaggtctgt ctggattgtg aaaagatttc   2220 

gactcttatt cagttttgat ttgtgtattt ctgaaactgt cctgcccttt taaaaaaatt   2280 

accatactac tgttttactg tacaggagat gtgattattt gggaccatag gtgatctttg   2340 

tacataactg tcctgttgtc aagtctggaa aacaagtcat gaaggtcaga ccctttatta   2400 

atcatcccaa aacttttaaa gatatttcaa aaaagttttt aaagtttttt ctttttctcc   2460 

ttagggtttt tcatatgata ttgtgcccat atatatggga aatgtcttag aaaacatttg   2520 

ttacatcaaa ccacctagtc aactggtaca actaagccaa gtacagctca gaaaatacat   2580 

tttacctctt cttttttggg tgtcccattg ctgaaatgga tacccattta gctgtcttca   2640 

catttgggga agtgtgtagt tagattatca actatatgcc tgggtctctt gaaaagtaaa   2700 

gttttttctt cagtacagtt tatacatgat tgaatgtagc ctaataatga agataagcta   2760 

tactttggct caagattgtc atcagaaaca aaattttcat tattcctgag acttgtatat   2820 

aattggtatg cttagcttta agttgaaagc atagctgtgc aactaaattt taaatccata   2880 

atttaggctg ggtgtggtgg ttcatgcctg taatctcagc actttgggag gctgaggaag   2940 

gatgatcgct tgagcccagc agttggagac cagcctaggt aacatagtga gacctgcctc   3000 

tacaaaaaac agaaaactta gccgagaatt gtggcacatg tctccagtcc tagctacttg   3060 

ggaggctgag gcaggagaat ggattgagcc cagaaggcag agattgcagt gagctatgat   3120 

cgcgccacta actccagcct gggtgacgga gcaagaccct gtctcaaaaa aaaaaaaaaa   3180 

aaaaaaaaaa aaaaaaatca tcatttgaca cgtattttga ttttaaaatt ttagtataaa   3240 

tgttctcaaa aagtctattg actcagtatt gaatcttggc tttccaattc tgccataagt   3300 

ttttcttttt tgtggagatt ctcaggaatc atcttgtgat aggatatttt aaattctagt   3360 

tgctcggtgg atacacagaa aactgttaaa tttgtttaca ttagggaacc tcgaacacaa   3420 

ataccatata agttagtatt tgttctttca tatgaaatat tttaaatgct ttttaaggat   3480 

atcttgtgca atctactgat ttagtaccat cagaactttg atttaacaaa aaaaaaggtg   3540 

aaattagtta aaaattaatc aacagtttaa catctgtgtc tgtgactctt tagttgggga   3600 

acatctgatg aaacaccgtt ttttatggtc taattactgc tgaactaaga gtataggtta   3660 

tgtttcagtt ctaaataaag tgggaatagg gagctgcaga aatgcttgat gatgttactt   3720 

ctcctgagta ctcatttttt aggtccatac tattctagtc tatgttttca ggtaatgtta   3780 

gactaccgtt taggacagag gaactacact ttataatgga agaaaaacat ttacttttac   3840 

cttaaattaa tgacatgcaa attgtttgat gtttggtgga agttttatac agtcttgcaa   3900 

aagtgaatag actgtttctt tcttatttac acttttaaat tcatgtctga aaatagttgt   3960 

tttagagttc tgtgtttatt taataataaa agttttagaa aagttatttg gaaccaagtt   4020 

ccaaaggaat aaaagttgca tatatgggaa gctagaacta aatcaagatt gggatttgaa   4080 

tgatgtagat aaaaattatg ggtcaaaaat acctactaaa atatgtaatg ccatcagggt   4140 

cccaatttag tatttaaaac aatcttcttt ttatttattt attttttttg agatggagtc   4200 

ttgcttgctc tgtcgcctag gctggagtgc agtggcatga tattggctca ctgcagcctc   4260 

tgcctcctgg gttcaagtga ttctcttgtc tcagcctccc gagtagatgg gattacaggc   4320 

gcgcaccacc atgcctggct aattttttgt atttttagta gagacggggt ttcaccatgt   4380 

tggccaggct ggtcttgaac tcctgacctc aggtgatctg cctgcctcgg cctcccagaa   4440 

aacaatcttc tttaataact ttgagaaatg tttttgtcgt tatataaatt ttctcacttg   4500 

tagttctttg ccttgaagaa aaaaaatcaa attactgctc tgtctgtggg catgaatttt   4560 

gaaagtgata aaggtttttc tactgggttg tcacttaaat tttggcttat gctgccctgg   4620 

agtgaccatt atgacttaaa aaaaatatat ttattgcact tgactggcag tgggacttat   4680 

aaaaatgtgc aagattgttt tgatatttgg tttagaattt ctctttcaat gaagggactc   4740 

cgagggaaaa caaaaattga gacataaaat aaatttttcc ttctaaaaaa agacttaagg   4800 

gaaaagacat atagataacc ttcaaatata attcagttaa catgaagaca tttacaaaat   4860 

tacccatgat tctatcagcc tcatataacc gttctttaca tttttaaacc aaattctaaa   4920 

ctaatctgtt tagtttttta aaacttaagg aattaagtta tttaggaaag ccattagaat   4980 

gaatgaaaag atatctacat gctacttcat tttgcttttt tggagaattg tatgtaataa   5040 

gttggtaatt tagaattaat ttgtattagt ttatatcttc caatgggaac attgcgtttt   5100 

ttagttactg cctggcctga cagtatgcaa agaggcctgg ggccctgtaa aggggacatt   5160 

tcctggaaga attctctgtt gtatatggaa aaaccctggc tcagagtaga tttcttgcca   5220 

aattgtctaa gctgatggat tctagttgaa taccattttg ctttataata tagccatcta   5280 

gtttcacatc ggtttctata ttcttaaaat acttgaggat ctacctgaaa ggtgaattaa   5340 

aatattatta atctaacaaa acatattatc ttatagtact taaaactaga atcttaaaaa   5400 

gtaatttata agtttttgtt gttgctaatg ggtaggggaa aaaagaccaa agtgataatt   5460 

ctgttttcag gaaggtaaaa ctaaaaagat aatttattta agatcagtat cctttccaga   5520 

cctgtttagt ctcagactgt tgagatgaac agcatttacc agacattcct accttctaat   5580 

tcagttgtct tggatactga atagaccctc attcttggct cattaacaaa acagatgtga   5640 

gaaagaatat tgtgtggttt ttcagccata atggttatgc tgttaggata catgaacagc   5700 

ctttctgtat ttggagtttc tgtggttttc tgccattatc tgtgttaata ttaatgactt   5760 

tctttggcta gccactgctt aaaaaaaaaa aaccaactat tgagattcag caaaaccttg   5820 

tcacacaact gatgctttct cttatacatt aaaatgtggg cattttgtgg tttggttata   5880 

ataaaaaaaa gtgtgcatta gtctgaaatg tcagtttaag gaaatgaaga attccttgtt   5940 

ttttgtttgt ttgtttgttt gagacagagt tttgctctcg tcgcccaggc tagagtgcaa   6000 

tggtgtgatc ttggctcagt atttttagta gagatgggat ttcaccatgt tggccaggct   6060 

ggtcttgaac tcctgacctc aggtagtcca ctcacctcgg cctcccagag tgctgggatt   6120 

acaggcatga gccactgcac ctgccctaga attccttgtt ttacatcagc cagttatttt   6180 

atacatcatt tccaaattgt caagttcttg ggaaatcaga acgtggtatc tacagtctat   6240 

tgatgtgaga catttttaga ttaaaaaaat attttttgta gagacgggat cttactatgt   6300 

tgcacaggct ggtcttgaat tcctaggctc aaatgatcct cctgcctcag cctcccaaaa   6360 

tgctgggatt gcaggagtga gccaccatgc ccacccatat ttttaggttt ttcatttgta   6420 

gaagaaattt tacaagaatg tgttctcaat tgtaagctta cataatacta cttttgagtc   6480 

attactaata cttggtattt taactgattt ctgaatcttc taacaatatg agagagacat   6540 

agtatttctg tgaactttaa aaatgatgaa agaatagatt gcaaaatggg ctcttactaa   6600 

taacaaggga aatgtcccct tttattttca agggaggaaa tgccttttaa aaattgtttc   6660 

tcactcctgt aatctcagtg ctttgggagg ccgaggcagg tggatcagct gaggtcagga   6720 

gttcgagact agcctgacca aaatggtgaa acctcgtctc tactaaaaat acaaaaaatt   6780 

agccgggcat agtggcgggt gcctgtaata cccgctactc gggaggctga ggcaggagaa   6840 

tcctttgaac atgggaggtg gacattgcag tgagttgagg tcacggcatt gcactccagc   6900 

ctgggcaact caaaaaaaaa aaaaaattgt ttcccagccg gatgtggtgg ctcccacctg   6960 

taatcccagc actttaggag gctgaagcag gcagatcatg aggttaggag ttcaagacca   7020 

gcctaaccaa catggtgaaa ccccatctct attaaaaata caaaaattag ctgggcatgg   7080 

tggcgtacac ctgtaattca gccacttggg aagctgagac aagagaattg cttgaacctg   7140 

ggaggcggag gttgcagtga gccaagatcg tgccactgcc ctccagcctg gaccacagtg   7200 

cgagattctg ctcaaaaaaa gaaataaatt gtttcccata ctgccacctg ataagcttaa   7260 

ccctcaactg gctggatgtt ctataagtga ttatttaatt gtaatgagcc taataataag   7320 

tgcggtatgt ttggacagat tcattgaatg aaaaagtgga attagcaggt aggaggttcc   7380 

tgaagttcca tgctgtttac tacgtagctt tgcagactta acatgtataa aatcagagac   7440 

atttcattaa gtcagatttt gagatcaaca caatatattt ctttttccaa aacaaaaatg   7500 

tattcttttt tttttttttt tttgagacgg agtcttgctc tgtcgcccag gctggagtgc   7560 

aatggcatga tctcggctca ctgcaacctc cgcctcctgg gctcaagcaa ttatcctgcc   7620 

tcagtctccc tagtagctgg gattacaggt gcccgccacc acgtccagct aatttttgta   7680 

tttttagtgg agatggggtt tcaccatgtt agtcaggctg gtcttgaacc agacctgacc   7740 

tcaggtgatc cacccttctt ggcctactga agtgctggga ttacaggtat gagccactgt   7800 

gcccggccca aaaatgcatt ctttttccaa ttataaaata ataactacat gtttattact   7860 

ttaaaaaaca aacgatataa gaatgtctca aatagaagat gaaagtatga tcctatcctc   7920 

cagatgaaac cattgttaac tctttcttgt atatcttccc agacatccat ccgtctgtcc   7980 

atatatttat catacgaatt gtttctaacc ttctttttcc acttagtaat gtgtcgtaag   8040 

tatctttccc atatcattac ttacatctat ataatagtat aataatttat actgagtaca   8100 

tagcatttaa ttttatctgt atattgatca gtctcattga tagtggttta gattttttcc   8160 

agttttttgt tattatgact aaaactttgt aagtattcta gtacatatgt gtttgtatac   8220 

tggtccagtg cttgcttttg gataaattgt tagaagtaga attattgaaa cagtattcca   8280 

tgaatattaa agaaaatgtt tccagtgaaa atctataagt tagtaattgg ctatagtata   8340 

tgttatagtt gattttgatt tattcactgc ttgttttttt tcatcagtca catttgctgt   8400 

aggctattgt ttagctttag actttccaac tggtacacat tggattacta gatgagtgaa   8460 

caacatggac acatgtatgc tttggaaatg tatggtttta tgtttgaaat ttagtttggt   8520 

tagttattat ccagtacata caataactgc tgaaagaaaa gtttgatata gggagaaagt   8580 

ccagatagtg ctttgtattt ctgtgtagtt atatttccaa ctctagtggg cagtatgtat   8640 

ttgttaaata actaaaatat gcttcattgg aagtataatt cattgtattg acagaattgt   8700 

ttcatctgct aatttacatt attatgtaat gtaaatattt cataatattc tggatattat   8760 

gaaaatatcc agaatatttt ctggatacta aacttgatta gtatctatag aattctgttc   8820 

attgcttatt catgcaacag aattttgctt tgtgccaaat tatttaaaaa gcaccaggta   8880 

aagtaatgac catggagaaa aaaattgaca gtatgatata gtgtaaaaaa catgggtttt   8940 

agagacagat tctggctctt aaattaactg aaatttatta atgatgtgtc ggtataggtt   9000 

tgagtgcaaa tgttctcctc ttgtagagga tgttgatagt agggtgtctg tgtgtatgtc   9060 

agggcaggag gcctgggaca tatgggaaat ctctaccttc tgttcaattt tgctgtgaac   9120 

ctaaaacttc cctaaaatag tctatcagaa aaagttaact gctactttgg gcagtgcatt   9180 

taatcttcct taaccttaat tttcttatct gtacaatggg atagtaagaa gagatgacac   9240 

atgcaaagga aatggccatt tctctctttt ttatgatatt ttactataga gaatttagga   9300 

tgtatacata taggcagaac tgtataataa actctattgt acccaccacc caaacgcagt   9360 

catcaaccca cgtccaatcg cttctcttct acttttccct cttttatatt tttgaagcat   9420 

attctaggta taatatgatt ttattcatat ttagtagtaa ctataaaagt tatggactca   9480 

tgatatagta ccattatcac agcaaaataa taatcactta taaaaatttc taatcattgt   9540 

tcaaattttt acttgtctca catattattt tttaaactgt ttgccttaaa aaaaaatttt   9600 

tttttttttg agatacagtc tcactctgtt gcccaggctg gagttcagtg gcatgatctt   9660 

ggctgactgc aaccttcacc tcccaggttc aagcgattct cctgcctcag cctcctgagt   9720 

agctgggatt acaggcatgc gccatgacgc ccggctaatt tttgtatttt tagtagagac   9780 

ggggtttcac catgttggcc aggctggtct tgaactcctg acctcaggtg atccgcccgc   9840 

gtcagcctcc cagagtgctg ggattacagg catgagccac cacgcccagc ctaaaaaaaa   9900 

tttttgattc aaaatccaaa taagttctac acattgtgat tgatcgatat gtcttttaag   9960 

tgtcttaatc ggtaagtttt ctctccttgt ttttctcctc tgcaatttat gggctgtttg  10020 

tccttttaga atttttcacg atctggattt tgctggttcc atctttacaa tttaatttaa  10080 

cataatcctt tgaatttcct gtaaactgct agtggatcca agggcttgat caaattcagg  10140 

ccattctttt tgaacttact acagttgggt ttttgtccct agcacttgac tggaattgtt  10200 

tttatcaagg tcagcaaaga cttagctaaa cccaatagtt cccagatctt cattttattt  10260 

catccacatc taatgacatt ttcttcttga aacactgttt ttctccattt ggttttcagg  10320 

gtaccactct ctccaggtcc tcctccaacc ttgttggctg ttacttttcc agttcctttg  10380 

ctgttttcat ttccctaatt tctaaatatt gggagtatcc ttggggttag tattctgtat  10440 

ccatgccaca gtctgtctga tctctaatcc agtggtttta aataacactt ctatgctgag  10500 

gacacccaca tttacacctc cagcctggac ctctcctctg aactccacac tcatctaact  10560 

gcttactatt catctacttg tagacacctc aaatttagca tatccttaaa atcctcttga  10620 

tttcccctcc aaacttgcta ctatcactga gtctttccta tctcagtaaa tgacacttct  10680 

gttctttcag ttgtacagac caaaaaacct tgagaatgtt tctcctcata ccccacatct  10740 

agtccattta acaattcctg tcaggcctac cttctaaatg ttttccacat ccacatcact  10800 

cccctaactg tactactgta gttctagcca acattatctt tcacctagac agccacatag  10860 

tctgctgact ggtctccctg cttgtaccct tatgtataat ttttcataca gcagctggag  10920 

tgatacttaa aaaaaaattt aagtcagatc ataacacttt ttcactcaga actcagaggg  10980 

ctgacactat ctaactaact tcaagactca caataaagct actgtaatca agataatgtg  11040 

gtattggtga aagaaacaac taatggaaca gaacagagag tccagcatgg caggttacca  11100 

tcccaattct cctacttact agctataaaa attttaggca aattatttca gttttcctca  11160 

tctgtaaaat gattccttcc tttatagggt tggtatgaag attaaatgag ataatgcatg  11220 

taaaagcacc tagcaggcca ggcttggtgg ctcacacctg taatcccagt attttgggag  11280 

gccaaggtgg gcagatcagt tgttctcagg agttcaggac gagcctgggc aacatggtga  11340 

aaccctgtct ctaccagaaa tacaaaaact tagccctgca tggtgtaaaa taaaagcact  11400 

tagcacattg cctgagacat agtcagaact tgataaattt tagaatttgt ggattttcta  11460 

agttgatctt gacaagtttc ataagaaaga ggcagatcaa gtattatttt cattttttag  11520 

atcaggaaac aaattcaggg acagtatttg gtgacagtca aatgattaga taattggcag  11580 

agccagtact aagggctagt acggaatttg tacagtatta cttatctcag gctaggatag  11640 

gaaagattat gccctctgaa gagattttta aaaaaacaca aagcggaatt taaaaacaaa  11700 

tgattcaggc agcattttag tctcttttca tctacactga ataaaagtta ttgttagccc  11760 

aattttttat tcctgataca aactcattct tttgatatat tgttggattt aatttaacat  11820 

tttgttagga tttttgcatg tatattcgtg aattagatta gcttatgatt ttcctttttt  11880 

atagtgtttt tgtcaggttt tagtaccaga atttttctgg catcataaat tgtattgggg  11940 

tgtgtttact tcttttctgt tctctggaag tgtttgtata acatcggtgt tatttttttc  12000 

cttaaatgtt tggtataatt ctctagtgaa gccatctgga tctggaatct ttttgtatgt  12060 

atgtggaagt attttaaatt gtggatttaa tttatttgga ggacttttaa gattttttta  12120 

atgtaatttt tagtttattc agataatagt ttattaattt attgtttgaa ttttgattaa  12180 

caaagctgta ttttgagctt caaaaattta gtgctggaca tcacaggttt tctttaaatt  12240 

tttttgatta aaaaatgtaa aatatacaac cattaaattt accatcttaa ccatttttgt  12300 

gtatagtcag tagtgttcgg tacattcaca gtgttgtgca gccaatctgc acaactcttt  12360 

tcattttcta taactgaaac tatatccatt taacaaatct gcatttgctc atatctcaac  12420 

tcccggtgac cacacgtcta cttcctgttt cttatgaaat tgactactct aggtacctca  12480 

tgtaagtgga atcatataaa ttatatagtg tttgtcattc tgtgactggt tttgtttttt  12540 

tttttgagac ggagtctcgc tctgtcaccc aggcgggagt gcagtggcat gatctcagct  12600 

cactgcagcc tccacctccc aggttcaagt gattctcctg cctcagcctc ccaagtagct  12660 

ggtggctaca ggtgcacaca accacaccca ggtaattttt ttgtattttt ttggtggaga  12720 

tgatgtttca ccatgttggc caggctattc tcgaactcct gacctcaaat gatcctcccg  12780 

ccttggcttc ccagagtgtt gggattacag gcgtgccatg cccatctttt tttttttttt  12840 

ttttgggaca gaatctcact tagctgccca ggctggagtg cagtggcaca atctcggctc  12900 

actgcagcta ctgtctccca ggttcaagca gttctgtcat cccagcctcc caggtatctg  12960 

ggattacagg tgcctgccat catgcctggc taatttttga attttagtag agacagggtt  13020 

tcaccatgtt ggccaggctg gtcttgaact cccaacctca ggtgatccac ctgccttggc  13080 

ctcccaaagt gctaggatta caggtgtgag ccaccacccc cagccctttt tttttttttt  13140 

ttttaagtaa aagggtctcg cgctatcacc caggctggag tgcagtggca tgatctcggc  13200 

tcactgtaac ctccacctcc ggggctcaag cgattctacc acctcagtct tctgagtagc  13260 

tgggactaca ggtgcacacc tggctaattt tttgtgtttt tggtagatac aaacggggtt  13320 

ttaccatgtt gcccaggctg gtcttaaact cctgagccca agcagtctgc ccacctcggc  13380 

ctcccaaagt gctgggatta caggtgtgag ccaccatgcc cggcctgtct tatttcactt  13440 

aacataatat cttcaaagtt aatcatgttt tagtgtgtgt cagaatttct tttttaaggc  13500 

tgaataatat ttcattgtat gtatatacca cattttgttt attcattcat ctatcagtgg  13560 

gtacttaggg tgtacaaata actcttcaat cagttctttc tgctttcact tcttttgagt  13620 

gtatacccag aagtagaatt gctagatcac atggcaattc tgtttttcat tttttgagga  13680 

accatcatac tgtttttcaa agtgagtgta ccattttata gttccaccaa cagaggactt  13740 

ttcaaatttg atgaataata cttttttttt tttaagacag ggtcttgcca ttttgcccag  13800 

gctagtctca aactcctaag ctcctaagcc tcctgagtgt ctgggattac aggcacaaga  13860 

tgctgtgcct ggctatatag tactttagtg tatcagtaag ttttatttct ctaggaattt  13920 

gtctgtttca tcaaactgtc aaatttattg acacaatgta atgtcttcag tagctgtagt  13980 

gacttttttt cacttctgtt attagttaag cccttttcct cctttttaaa agaaatcagt  14040 

gttgcctaga ttttatcaat tttatttact tttttttttt tttttttttt tggtaagaca  14100 

gagcctcact ctgttgccca ggctgaagtg cagtggtgcc tcagcctgct aagtagctgg  14160 

aactacaggc ctgcaccacc atgcctggct aatttttgta tttttttaaa tagagacagg  14220 

gtttcaccat gttggccagg ctggtcttga actcccaacc tcaggtgatc tgcccgcttt  14280 

ggcctcccaa agtcctggga ttgcagacgt gaggcactgc acccagccca cttatctttt  14340 

tttgtttttt tgttacgggg tctcactctg tcacccagac tggagtgcat aatcttggcg  14400 

cattgcaaac tctgcctcac aggctcaagc cattctccca cctcagcctc ctgtgtagct  14460 

gggaccacag gtgtgcacca ccacactcag ctaatttttt gtatttttgg tagagatggg  14520 

gttttgcctt gttgcccatg gtggtctcaa actcctgagc tcaggcgatc cacctgcttt  14580 

ggcctcccag agtcccaaag tgctgggatt acaggtgtga gctgccatgc ttggcctgag  14640 

atacttacct tgtcaaataa tcaaataatt gattctgtac tttcttgatt cttttttatt  14700 

acatattgct tcttatttta ctcttttctt ttcttttctt tttttttttt aaatagagac  14760 

aagttctctc tctggcactg agtctggagc gtcgtgttac tatcatagct caagtgatcc  14820 

tcctaccttg gcctcctaaa gcactaggat tccaggcatg agccaccatg ccctgccctt  14880 

tcttctactt tctttaactt tactttgcta ttggtctcac actctttagg tctgacttgt  14940 

gcttgctcat ggtcagcttg gtttgtgtga ttgttcttcc ttctctctgc cctttccaga  15000 

acagttttcc agaggcatac ggttttctgt gtttattttt aatgaagaga ggaaatctgg  15060 

ggtgacagaa gttgaagtgt tagaaatgat gtcatcttgc agaactaggt tttagccatt  15120 

atcagctgta cttataattc taatatactc tggttgacaa ggctttggaa tacagcttgt  15180 

aactgtgact cttttttttt ccctttcccc tggcaggacc cgctggggcc cagcccctac  15240 

tcatggtgcc cagaagacct ggctatggca ccatgggcaa acccattaaa ctgctggcta  15300 

actgttttca agttgaaatc ccaaagattg atgtctacct ctatgaggta gatattaaac  15360 

cagacaagtg tcctaggaga gtgaacaggt aagaatcatg aaactgcaaa gatcttttgc  15420 

tatttttttc cttagtaatt atccatgttt attttgtata tctgaataac aattacaatg  15480 

tgtaacagtt tgaccaaaaa catctggtaa tttgttttaa aactgattgt acttcagggg  15540 

tgtgatagtg gggaaaaaat ctttgaaatt attttgttat aacacgagct cacattttcc  15600 

ctgtgataat agaaaaggtt caagttattt ttacatgctc ctgaaatcag gctgcacatc  15660 

atgagcacat cattttcctt gctgttaggt aatatgtcca tgcttgcttt tttctcctca  15720 

cctctcttat gtaccacttt cataatgttc cctttaagat gacggtggtg atgatagcag  15780 

ttgggggtag aaatactggt ttcatgcttt cttttctcct ttcccaattc ccaactgttt  15840 

cttaccatta tataggaata agtacagatg gtatataaag atttatcagc ctgctttcag  15900 

taagcttcct ctcgcctccc ccaaatgcca tttatattct tggatgtggt ttcggtaata  15960 

caggaaatat aagaggaatt tatgattgga tatatactat gtctatttgg attttgtttt  16020 

taaaaacaaa gacaacacat tttaaaaaaa tgtgatattc agtttagcat tttggtttct  16080 

atgatcccag cctcttctta ttcattaaat gttattaaga gtcttcattt aagacattta  16140 

agaaaaagaa tgttgtttct ctcaagaaat ttgtaatttg gtagaggaaa taagacatgt  16200 

aagaagtatg aaggtctttt tcttggactt gtcatcctaa ttgttagtat ttctgttata  16260 

cctgaaagtg aatgagcact aaaagacttt gtgataacac gttaaaaaca acaacacctc  16320 

taagaatgtt gtaattaaca tgtaatgcag agttctttgt gaggtcagga agactcgtag  16380 

agtgttacag ttgaaaggaa cctcttaaga agttaactaa tccaatacct tttttattta  16440 

tagctgaaat ccagaaaggt taagggattt agtcaagaac acatgtttca agtaggaaag  16500 

gtgaaaccag aactccagaa tcctgacttg gtagtcatta ggaagtattt tgtaaaggaa  16560 

gaagttaatc taaaacaatt ggtaaaattt tggttagctg tagtaaaaat aacatacata  16620 

taattttatt tatttattta tttatttatt tttgaaggaa ggatagcagt aacaaaagca  16680 

taacggttga gaagaaccag gtgtattgag tctgaaccag gcttaagggg aaggttcttt  16740 

gcattacatg ttaattacaa cattcctata ggtggttttt tttttaacat gttatcagat  16800 

actgctttaa gatactatct gttgaataga tgactcctaa tcttgctgta gcctctacct  16860 

ctttcctaaa cttcagattg acacccaaat gttcctaaag tgaacaacac aagtcaaaag  16920 

agtagtgccc tactcttctg tgacctcgta gtacttgatg tacacttcca ttgtggtgtt  16980 

tttagtgcat tgtggttatt tttctccctt tctccagtat aaccccttca tgaaaagtag  17040 

tgttttttat catctttgtc accccatgtc agctcagtga ttggcacata atactcagta  17100 

aagtgaatga aatgtttata aaatggcatg agtgtgatgg tgggggacag gaaagaaaac  17160 

tggatgttct agagggctgt tttcctgaac atgggttttt cagtgccgta ctcttatctc  17220 

ctaggatctt aggctagtct tggttttggt cttccttcac tctcttttat gtctttctgt  17280 

gagccgtcat ccacttatgg ggacttaact gactcatgct gtactctcat agagattccc  17340 

tttttcttgt ttctcaaaac tggttcatta atgtatagat ttgagtgaag gataatcctg  17400 

acccttctgg tagatattta cactttaaaa aggcatttat tagctgagcc atgggcctgt  17460 

agtcccagct actctgaagg ctgaggcagg aggattactt aagcccagga gttaaggctg  17520 

cagtgtgttg tgattgtgcc tgtgaacagc cactgcactc cagccggggc aacatagtga  17580 

gaccacatat ctaaaaaata aataaataaa aataaaaagg cattagttaa tctaagtaaa  17640 

gatctggggc ttgagggatg tcaattcaag tttttttagt atgccagatg agttacaagg  17700 

aaatgatatg gtggcaaaaa tattaagtaa aaggaacaga attttttttt tttttttttt  17760 

gcaacagagt ctctccctgt tgcccaggct ggagtgcaat ggcgcgattt ccgctcactg  17820 

caacctctgc ctcctaggtt caagcaattc tcctgcctca gcctcccgag tagttgggat  17880 

tataggcacc tgccaccatg accagctaat tttttgtatt tttagtagag actgggtttc  17940 

tccatgttgg cccaggctgg tcttgaactc ctgaccttgt ggtccccccc cgcccccacc  18000 

ccaccgccgg cctcccaaag tgctgggatt acaggcgtga gccactgtgc ccggccggaa  18060 

cagaattgtt tattagattt attctttctc ctgcctaaca tttttgtttt attttttggt  18120 

agggtgtggg taaaggaaaa tttgtgtatt atatatgtgt aattatatat gtgtatataa  18180 

agttgtgtag catagaattt catgtgtata tgctcaatgt attaagtttg tgagaaaaat  18240 

atgtgtcata aattggtgtg gtgcattctg gttttaactt acgattcttt tgacatcctt  18300 

aattacatta catctttagg ttgctttatc ttacattttt ttgacagtac caataattta  18360 

gatttgtaat ttaaatgttt ccaagtggaa agtttttaaa tttttgtgat gtaaaatttt  18420 

agtcattttt atcatgtttt tgagttttta tttattttat tattatttta tttatttatt  18480 

tttttgagat ggagttttgc tcttgttgcc caggctggta tgcaatggca cgatctcggc  18540 

tcattgcagc ctccatctcc tgggttcaag caattctcct gcctcagcct cccgagtagc  18600 

tggaattaca ggcatgtgcc atcatgccca gctaattttg tattattagt agagatgagg  18660 

tttctccatg ttggtcagtc tggtctcgaa ttcccaacct caggtgatct gcctgccccg  18720 

gcctcccaaa gtgctgggat tacaggcgtg agctaccgca cccggcccaa gtttttatag  18780 

gaactgtagg acttgtttgg gattctaaaa atcatataaa tcagctttat actttgttaa  18840 

taatattgct ttgatttaat gtcaacatct gcaaaactta ttccgttttc ttcagctgac  18900 

ttgcttttgt cttcagtttt tacagtatta ctgcatgact agtcagttga aacttggtgg  18960 

tcttctgaaa ttgatgtggt ggctcagttc ctgtgcttca acaactggaa ttctaggcgt  19020 

tagaaggaac tagatagaac ttaacaattc cttttcaata ttagcaaaac agttaaggga  19080 

caaaatgcag tggttcagtt atgtctaatt taacttattc aaaatattaa aacaaaacaa  19140 

attgttttat ttcctttttt aaaagtcagg gtctcaatct gtctcccagg ctctggaatg  19200 

cagtggcaca atcatagcac actgtgttct caacctcctg gactcaagtg atccttccac  19260 

ttaagcctcc tgagtagctg ggactacagg caccaccaca ccaagatcat tttttaaaat  19320 

ttttatttgc aggagacgag ttctccctat gttgcccagg ctggttttga actcctgagc  19380 

tcaagtgatc ctcccaaagt gctgggatta caggcatgag ccaccatggc cagccttatt  19440 

tcgtttctta ttaaagattt atattggcca ggcatggtag ctcacgcctg taatcccagc  19500 

actttgggag gctgaggcga gtggatcacg aggtcaggag atcgagacca tcctggccaa  19560 

catggtgaaa ccccgtctct actaaaagta caaaaattag ctgcatgtga tggcgggcgc  19620 

ctgtaatccc agctactcgg gagactgagg caggagaatt gcttgaaccc agaaggcaga  19680 

ggttgcagtg agccgacgtc gtgccactgc actctagcct ggcaacagag taagactccg  19740 

tctcaaaaaa aaaaaaaaat tatattgttg ccttctataa agtcatagtg attctcctct  19800 

aagtgactta aatgttttaa tacttaaatt atcgtgcatg aaatttttct tgtccatatg  19860 

ccacatgaac aaatatttgg cactaaggca ttaatcataa tagtagaaag atgtattata  19920 

gccaaacaat tgccacttta gttggagtct tcttagacac aatatccagg aaatgctagt  19980 

gaatcatttt gtgggtcaac ctttctacaa atttattctt tagattttct gtccattgct  20040 

ttttttgtcc tttcctcacc ccgttttgtg ttggggggcc aagttgggga aggagattct  20100 

ttccttcctt cttttccccc tattaaatga ttttgattga atgttagctt ttgttaaaag  20160 

agtatgtatg ttaagtatat ttcaaatgtt actagtttct aataggtgaa tggtctcaat  20220 

gactaaaaaa caaatatttt ttagaaacat tatgacctag agtatacatt ctgtaacttg  20280 

agattttatg ctagtttgtc caacctctaa atacaccttg aatagatagt atatgtattt  20340 

attcaaaacc attaaataat ggaatagata catgttaaaa attatgtata caacatgatt  20400 

ataactgcaa tatctatttt aaaacatgaa taaaaatttg aaggaatctt aaaatagtag  20460 

tagattgtgg ttgcattttt attttattta tttatttttt agacagagtc ttactctgtt  20520 

gcccaggctg gagtgcaatg gcacattctc agctcactgc aacctccgcc tcctgggttc  20580 

aagcaattct cctgcctcag cctcccgagt agttgggatt acaggcaccc atgcccagct  20640 

agcgtttgta tttttagtgg agtcggggtt tcgccatgtt gatcaggctg gtctcgaact  20700 

cctgacctca ggtgatccac ccacctcggc ttcccgaagt gctgggatca caggcgtgag  20760 

ccaccacacc cagctgtggt tgcatttttt tggctcagtt ttcttttaca aatgaaacat  20820 

catttttact actgttactg ttaatattct atgatgatta ataacatgcc aaatatttct  20880 

gcatatttca tattgatata atgtttaatg ctgatgattt ttattttatt tatttatttt  20940 

gaaacaggat ctcgctctgt cacccaggct ggagtgcagt ggtacgatca cagttcactg  21000 

cagccttgac ctccctgggc tcaagcaatc ctcccacctc agcatcctga gtagctgaga  21060 

ccaggagcat gcctggctaa tttttctact ttttgtagag acagagttta gctatgttgc  21120 

ccaggctggt ctcaaactca tgggctcaag acatccaccc accttggcct ttcaaagtgc  21180 

tgggattata ggtttgagcc actgcaccca gacagatgat tgaattttag aaagaaaaaa  21240 

gtaaatctat attgatccaa ttttggcttt ttaagtggaa atctcagagc agcaatgtgt  21300 

ttaaagaaac ttcttttctg ctgttaggaa tgtcattttt atggtgttat agttggatag  21360 

tatgccaaga gggggcatat ttcattttga ataacttgat ggatatataa tttacatgcc  21420 

ataagtcacc cattttaaaa tgtacacctc agtggttttt agtatattgc cagagaggat  21480 

gtacagccgt cacttcaatg taattttaga acatttcatc ctctcaaaaa gaaaccccat  21540 

actcattagc agtcactgcc cattagtccc tccccacagt ccttgccaac cactaatcta  21600 

ctttctttct ctgtagattg tcggttctgg gtcggtcttt ctttctttct ttctttcttt  21660 

ctttctttct ttcttttttt tttttttttt tgacagagtc tcgctctgtc acctaggcta  21720 

gagtgcagtg gcgcgatcgc ggctcactgc aacctctgcc tcctgagttc aagcagttct  21780 

cctcagcctc ccaagtagct gggactacag gcgcctgcca ccatgcctgg ctaatttttg  21840 

tatttttagt agaggtggga tttcaccatg ttggcccagc tggtctcaaa ctcctgactt  21900 

caaatgatct gcctacctcg gcctcccaaa atgctaggat tacaggggtg agccactgca  21960 

tccggccgga tatttcttat aaatggaatc atataccatg tggccttttg tgactggctt  22020 

ctttttgcat aatgatttca aggttcattc atgttgtagc atgtatcagt atattcaggc  22080 

actgcataac ttttcagtga attacagacc acatgtatga tggtggtccc ataagattat  22140 

aataccgtat ttttactgta cctttttatg tttagataca caaataccac tgtattacag  22200 

ttgcctacag tattcagtat agtaatgtga tgtacaggtt tgtagcccag gagtaataag  22260 

ccataccata tagcttagat gtgtatatgg cttagatgtg tagtaggctc tactatctag  22320 

gtatgtgtaa gcacattcta tgatgttcac acaacaaaat gataatgcat ttcctggaac  22380 

atatccccat cgttaagtga tgcataactg tactttattc ctttttattg ctgaataata  22440 

ttccattgta tggatataat acattttgtt tatccatcat ttgatggaca tttgggttgt  22500 

tgccattttt gactactaca aataatgctg ctataaacat tcatgtacag gattttgtgt  22560 

ggacatacat tttcatttat gttggatata tacctaagag tgatatcata tgataactct  22620 

atatttaacc ttttgagaaa ctgccagact cttttccaaa gtggctgcac cagccagaca  22680 

tggtggctca tgcctgtaat cccaacactt tgggatgctg aggtgaaagg atcacttgag  22740 

tccaggaatt caagaccagc ctgagcaatg tagcaagaca tcatttctac taaaaagaaa  22800 

aaaaaaaaga aggcagtgtc tgcaccattt tacattccca ctagcagtgt atgaagatgt  22860 

tttcccatat tctcaccaat atgttattat ttgtcttttt aaaaattatt ttcatcctag  22920 

tggatgtgaa gttgtatctc attgtcgttt tgacttgcat tttcctgatg acggatgttg  22980 

aacatttttc atgtatttat tggtcatttg tatattttat ttggagaaat gtctatttag  23040 

gtcctttgct aatttttttt ttttttttga gacagagtct tactctattg cccaggctgg  23100 

agtgcagtgg cacgatctta gctcactgca acttccacct cccaggttca agcgattctc  23160 

ctgcctcagc ctcccaagta gcataccacc atgcctggct aatttttgta gtttttagta  23220 

gagatggggt ttcactatat tggccaggct ggtctcgaac ctctgacctc aggtgattca  23280 

cccgcctcac ccttccaaag tgctggggtt acaggcatga gccactgtgc ctgcctgccc  23340 

atttttaaat tgggtcattt gtctttttgt tattgagtca taggagttca ttatatgttc  23400 

tagataaaag tcccttatta gatatatggt tgcaaaattt ttctctgttt atacatgttg  23460 

catcttcatt gtcttgatgg tgtcctttga agcacaaact tttaaaattt tgatgatgtc  23520 

taacttattt tttcttttgt cgcttgtgat tttgttgtca tatctataga agggttctat  23580 

attaaaatga tttagacaac atacttcaga aaacactacc agtaaaaacc aaatggtata  23640 

gttttgagtg tttagtgatc ttggggaaac tattatacaa aatatgtcag ctaataaata  23700 

agttttattt tccttttagt cacttggaag ataggaaagt taacagatgg taattatttc  23760 

acatctcaaa attcttttag agtggcatct aaatacaata ctaagtagaa attagccttt  23820 

tgactaatat tcctataata tatttgaaac ttgaagatac tttcataaat taacaaatat  23880 

ttacacacaa gggactagta cataaggtat tattaccaac atctatttgt gtagatataa  23940 

attacaatag ctgtatagtg ttctattata tgaatgtacc ttgatttgtt tactttaacc  24000 

tgctccagtt tgttaggtta acttaaatct atttaaacca tttatctgaa cttaccacat  24060 

gtttatacca aagtactatg ctattggtac tagatttaca ggatatacgg aaacttaaag  24120 

atcatttttg aatcttctct atgttttcat taactgttta ctcctgtttt gtgtcaggca  24180 

ctgtgctagg ttctagcaat aatacaatag ataaaacatg atctctttaa agttttaaat  24240 

tccatatgga gtgacaaatt ctgtgatatg cacattatgt actgtgatga aagagtaatg  24300 

attcctgcct ttgggtaagg aggaggatgt ggtgtatcac atggtatttg agcaaaataa  24360 

ttgtatcata aaaggtacag taaaaatata tcatcttatg ggaccaccat catatatgtg  24420 

gtctgtaatt gactgaaaag ttatgcagca cctgcctgtg ctgatatatg ctacaacatg  24480 

aagttgtcca gtggacaggg agaaagaata atccacatag acagcatgag caaaggtatg  24540 

acatgttggt ataacagaaa caggccagta taaatagagt agctagagat gagtctgaag  24600 

agttagctag ggagtaggtt atgaagaatc tgaaatccgt gctaaggctt gtgaattcag  24660 

aaatagtaga gagccaatag aaccttttaa acaaatgaag aatatcggta tttaggacca  24720 

tacttgatga cagtgtggtg aatgagagat gagaaagact tgagtcctgg agaacatttg  24780 

gaaggctgtt gtagtagtct aggttagcgg tcttcaaacc attgatcaca cgtccccatt  24840 

aattaaaatt tgtttgacca aaaaatacat atagatataa atgcacacac atttcaaaaa  24900 

ctataatttg ttggcgtgta ctactgtttt aatatgtaac tgtagaaaaa gatgagaaag  24960 

ataattttga aatgaactat ttaaaaatac atttaaataa cttaaacttt tcagattaat  25020 

ggtacaaaaa accctgactg aatatgtgtc acacacttga actacagaaa gttgcagtgt  25080 

gctgaaaatg aatgaacgag aggtacactg ttaacttttt tttttttttt ttaattgaga  25140 

caggagtctc actctgtcac ccaggctgga gtgcagtggc gtgaacatgg ctcactgcag  25200 

cctcaccctc ctgggcccga gcaatcctcc cacctcagcc ttcatagtag ctgggactac  25260 

aggcacatac caccatgccc ggctaatttt tgtatttttt atagaaatgg gatttcgcca  25320 

tgttgcccag gctggccttg aactccttgt ctcaagcgat ctgcccacct caacttccca  25380 

aagtgttgga attacaggcg tgagccactg tgtcagacct taactcttat gtgttgcaga  25440 

actcccatta ctctcctagg attcctggtg taccgtgtgt tgcacctgac catctaatgt  25500 

ggaataactg aaggcaccag tatcaatcca tactcatgaa tattagtaaa tcttaattcc  25560 

taattgttca ctgaaaatta aatataaata tgtctaattt ttcctcatac tgcagcatac  25620 

cccttggcac ctctggtaca tatttttctg gattataggt aatatgttca aagacacagt  25680 

ggcaataatg atgatggagg gcatagatgg aagatttaga aaaagaatga acaatttagg  25740 

tatgtaagga aaggatagag ataagaatgg cttcatagtt cctagctggt gcattagtaa  25800 

tggttttaac agaaatatag attctgaagg gaccaggttt ttgtatacta ttttgaatat  25860 

ttggaggttg aattgcataa gaaacatcaa aatggcagaa gttcaatagg ttattggaaa  25920 

taagtgtcta gctaagtgtc aggagataag tcaaaatgga gattgtgatt cgtcagcatg  25980 

taggtgatag ttaaaaactg gggaagtatg taaaaataaa agaactgaga ctagatctct  26040 

gagatactat tatttcaggt ttaccagtga aaacacacag ggattggaaa gataggagaa  26100 

ccaggacaaa gtagaagcta tttcagagaa ggcaaggtaa ggatcatgat tttctttttt  26160 

tgtttttttt tttttttctt ttggagaggg agtctcgctc tgtcgcccag gttggaattc  26220 

agtgacatga tcacgtgatc ttggctgact gcaacctccg ccttccaggg tcaagcaatt  26280 

ctgtctcagc ctcctgagta gctgggacta caggtgcatg ccaccatgcc tggctaattt  26340 

ttttgtattt ttagtagaga tagggtttca ctgtgatgcc cacgctggtc tcaaactcct  26400 

gagctcaggc agtccgccca cctcggcctc ccaaagttgc taggattaca ggcatgagcc  26460 

actgcacctg gccttaagga tcatgatttt caaggaacaa agtttgatta cagtggcaaa  26520 

tgctaaacaa agccaggcgt atagagactg aaaatgcgcc attacacatg gttgttaaga  26580 

agttggtggc ccagcctggt gcagtggctc acgcctgtaa tctcagccct ttgggaggcc  26640 

aaggtgggca gatcacttga acccaggagt ctgagaccag cctggccaac atggtgaaac  26700 

cccatctcta ctaaaaatac aaaaattagc tgggcatcgt ggtacatgcc tgtaatccca  26760 

gcttggatta cttgggaggc tgaggtacga gaattgctta tacccaggag gtgaaggttg  26820 

cagtgagctg agatcatacc actgcactcc agcctgggcg acagagcgag actgtctcaa  26880 

aaacaaaaaa aagaagtcag tggcctgata aaaataattc acatatgaaa tgactacaaa  26940 

catagtgtat agtgaaatgc tctgtatgag ctgagctcag tggctcatgc ctgtaatccc  27000 

agcactttgc gaggctgacg caggcagatc acttgaggtc aggagtttga gaccagcctg  27060 

gccaacatgg tgaaaccccg tctctactaa aaatgcaaaa attagctggg cgtggtggca  27120 

cgtgcttgta atcccagcta ctcgggaggc tgaggcatga gaattgcttg aacctgggag  27180 

gtgaaggttg cagtgagcag agattgtgcc actgcactcc agcctgggca acagagtgtg  27240 

attccatctc aaaaaaacaa aaatgctcag tatcgatttt atattacaaa ttattaaaat  27300 

tttggccaag tgcagtggca catgtgaggc ctgtaattcc agcactttgg gaggccaagg  27360 

caggaggagt gctggaggcc agaatttcaa ggccagcctg ggcaacatag ggagacccct  27420 

tctgtatgaa aaatttaaag attagccagg tataatggtg tacacctata gtcctagcta  27480 

ctcaggaggc tgaggtgaga ggattgctca cttcaggagt tggaggctgc agtgagccat  27540 

gattgcacca ctgcactcca tcctctgggt gacagagcaa gatctgtatc tttaaaaaaa  27600 

gaaaaaagta ttaaaaattt gtcctggcca ggcgtggtgg ctcacgcctg taatcccagc  27660 

actttgggag gccaaggcgg gcggatcaca aggtctggag ttcgagatca gcctggccaa  27720 

catggtgaaa tcccgtttct actaaaaata aaaaaattag ccaggcatgg tggtgcgcgt  27780 

ttgtaatccc agctacccag gaggctgagt ctgaagaatc acttgaaccc aggaggtgga  27840 

ggttgcagtg agccgagatc acaccactgc actccagtct aggcgacaga ataagactcc  27900 

ataataaaaa aaaaagaaaa atttttgttc tacccagcac tttgggaggc tgaggtggac  27960 

agatcacttg atctcaggag ttcaagacca gcctgggcaa catgatgaaa ctctgtctct  28020 

acaagaaata caaaaattag ctgggcatgg tggcacactc ctgtagtccc agctactcgg  28080 

gaggttgaga caggagaatg gcttgaggca gaggttgctg tgagctgaga ttgcaccact  28140 

gcgctccagc ctgggcatca gagccagacc ttgtctcaaa aaaaaaaaaa gaaaaaagat  28200 

ctaaaatata atccctctct tctctgtttt gcatacctta aactttatct tgttgcacaa  28260 

gtatttattg gctaccttct ctgctagtaa ccacagagta ataaagataa gttagagatt  28320 

ggaaggatac aaagagagac tgccagctgt tttagttgtg ttttataaac ctctggatga  28380 

ttttgacatt ttgttatact ttagcaatct tctttctgtc tatactgtag tgacacattc  28440 

atttattgta gccatggata atgtcagtag acttttgggg aaaatattct ttcatgttgt  28500 

cttctgtaga ctagaataat atttttcatt ctgtcttttg ggagcagaga attaagaggt  28560 

acctaataaa gtgagatgga ggtggatctc tataagctta tagtaattac aactcacagg  28620 

aaaataattt gctctcctct tttttacatt aaagtttctc tcttcccatt tttctgctgt  28680 

ataagtcagg tggtaaaatg ggacttaatg aaattattat taaattttac tttataatct  28740 

gtgcaccaga gcatgatgga gtcaaaagag ttggtatcag aatgtaggaa gtagtgattg  28800 

aagtaagggt ggtaggatag gctgtacccc tttagaagat ctaatgtatt caggtagatt  28860 

tcatttttga agttattacc aattattctt aaggattctt aaattctcac gtgacgttct  28920 

aaaaaatgca tcacagtata attctgcaag aattcttttc ttctcagact aaggttatta  28980 

gtgaaaggaa gccactaaag attggttaga cattcttatc tgtgtttact cagattttat  29040 

ttcccaaatt actttcccaa gcactgtttt agaagttaaa atattttatg tatttttatt  29100 

agtctagttt tactacttac ggtaagctaa gaacttgttt aacaatatac acttaaatat  29160 

tttgctaaaa gtactgtatt tgaacaaaag attccactcc taaccctatt gttgtaataa  29220 

aagactagtg tcataaaata tagaggaaac tcagttatca gtttatgtta attaccagaa  29280 

ttattcatta tttgtgttaa tttactatat ttgatgctaa aacattgtag tgtattcatt  29340 

tgttatttgg aagacttcag tataattctt aaaatatatt tgtgagataa ttatgcttaa  29400 

attttaatat aaaaatatta ttatacatat ttgttttttt aatcttcaaa ttattttcac  29460 

taatattcca tttggttcct gagactgtta tctcattttt attgataaag aaactcaagt  29520 

cagagaagtt aaataacttt cttaacaact tagtgacaga atgggactaa aaactcatgc  29580 

cttcttattt cggtacttat attatcatat attttaaagg tttctcaggt tggtagtttc  29640 

ccaattccaa gtttcatcgt aatataatag cacctttgct actatagctg actagatggc  29700 

ttaggaaact agataaatta ctgttctaaa gagtgttttt tctctagctc cacatgccta  29760 

cctattaaag attctaataa actacccttt tccctaatat cctttgagat aagaaatgag  29820 

aatttactgt ccctagattt gccattttgt tagcttgcat actaaaatct gctggatgcc  29880 

catattccca gttactcaga aggctaaggc aggaggatca cttgaactca ggagttttag  29940 

gttacagtga actgtgatca catcactgca ctcaagtctg ggcaacagag caagacctgg  30000 

tctcaaaaaa aaattttttt ttttcgctaa aattctaaat atatgaattt ggccaggcac  30060 

agtggctcac acatgtaatc tcaacactct gggaggctga gacaggagga ttgcttgaac  30120 

ccaggagttg gagaccagca tgggcaacat agtgagaccc catctcttta aaaaaaattc  30180 

taaatatatg aattaattgt gtcatattag tgagaggtta aaaaataata taactcttgg  30240 

ccctcatgaa agatgactct ctttgtagca taggttttgt cagttatgaa cttaaaaaac  30300 

tgtcaagtgg aaaaattgac ccgtatacta tagaattcca gtgctatttc cttaaggctc  30360 

tgaactaaat tgtcaaatgt aagtgtaatt attcataaaa gtaatatcta atgccatgat  30420 

acgatttacc atgataaaat ttacaatgtt tcttttcttt tttttttttt atttttattt  30480 

ttttttgaga tggagtctcg ctctgatgcc cagggtggag tgcagtggtg cgatcttggc  30540 

tcactgcaag ctccacctcc cgggttcaca ccattctcct gcctcaggct cccgagtagc  30600 

tgggactacg ggcacccgcc accaagccct gctaattttt tttttttttg tatttttagt  30660 

tgagacaggg tttcaccgtg ttagccagga tggtctcaat ctcctgacct cttgatccgc  30720 

ctgcctcggc cccccaaagt ggtgggatta cacgtgtgag ccactgcgcc tggccattgt  30780 

ttggtatttt ttaaattaaa ttttactata agagggtatc gcggatattt cattttaatc  30840 

ttaaatttat atcttccctg acagttggtc atatagctgc tctttgaaca gttctagcaa  30900 

agatgaactc aggtacttta taaggtagtg taatttactt ttgaataact ctggtggtta  30960 

gaaaatcctg aaaatttcgt tccaaaatgt ctaatgttcc aactattttt cctagttctt  31020 

tctactcagt ttttcacatg acaatctatc aaaatagcca aaaacttatt ctgtaatttt  31080 

ctttgagttt ttcctattcc agactaagac tttcctattc caaaccagac ttggtttgat  31140 

ttatttttac tcatattaca tgatttccta tcaggattgc ctccttctca ttatatttga  31200 

atttttaggg tcttaaattt ttcacaaatt gaacagagta ctccaagatg taaaatgatc  31260 

tgttttaata tatggtggga tagttacctg ccttattaag tggattatct gagtacttaa  31320 

atatatgcaa cctcagtttt ttacttttga ggaagctaca tcatactgtt agctcatttg  31380 

gggcttgtac ccttttccac agcagcagtg ggtaagttga gattctctaa tttgttctta  31440 

ttacagttga agtgtttgga cgttaagtgt ttaggtatta cagttaccct tattatgttt  31500 

cttctttatt ttgttcattg ttgtagttgt tagtagcttt taacatagta atttatgttt  31560 

ttaacatgct agtcatgtct tccaagtatg tgttgttaga ggtttcttaa ccaacagata  31620 

tttattaatt acttactata tgtagggcac tagatatgtt tcctttccat atggtattga  31680 

tagttttcta aggtggaaaa ttattccagt gttcaagtat acttagaaaa agtagggaaa  31740 

cttaccctgc cccataataa acactctagt gaaaacatac gttactggcc aggcgccgtg  31800 

gctcacacct gtaatcccag cactttggga ggccaaggcg ggtggatcac gaggtcagga  31860 

gatcgagacc atcctggcta acacggtgaa accccatctc tactaaaaat acaaaaaatt  31920 

agccaggcat ggtggcgggt gcctgtagtc ccagctactc gggaggctga ggcaggagaa  31980 

tagtgtgaac ccaggagggg gagcttgcag tgagccgaga tcacgccact gcactccagc  32040 

ctgggtgaca gagcgagact ccctctcaaa aaaaaaaaaa aagagaaaga aagaaaacat  32100 

cttgtactgg cacaagaaca gacaaacaga acactgggac agtatagaga actcagattg  32160 

atttatatat gggaagtgaa tgagataaaa atgccattac aaattgatta gttaagtata  32220 

agccgtttag taggtggcat gaagaaacct gctcactaga tggagataaa taaaattggg  32280 

tccttgctgt ttataaagaa gaaccaaaaa atgtagacaa aactgtaaag ttaataaaac  32340 

ataatttatc tttttgactt tgtattagga aagtatttct taatacctca aaagcttgaa  32400 

gtcataaggt gaaatttaat ttgatgatgt tctcaaattc attagtaata agagaaatct  32460 

aaattaaaac atgcttttag tttataccga ttaggctaac aaaaattaga aagcagaact  32520 

ggataatgcc acatattggc tggacgcagg gaaataggag cctcaaggag tgcaggttag  32580 

tgtagtcatt cttgagaaca atttggcagt acatcattta cttgataaga ttcattttga  32640 

cctaacagtc tgtttctgtg tctgtaagca gagattaatt ctcacatggg ttcataaggg  32700 

gacatgtaag gagataattc atttcaacat tgtttttggg tgttgcaatt aaagatactg  32760 

tgaatctgca atgctggggg agtggataga caacatgtgg agtactttgc atcaatcaga  32820 

aacaatgaac caagtcactg aaattgtata caaccaattt tttacagata aatcttttaa  32880 

aaataataaa aataaatata ccataataaa tataccacag caacgtgaat aggttttaaa  32940 

acatctaatg cagagggtaa aagtaggtat acatagaaat agaagaatgt tcatcaaaca  33000 

aattagaaga ataacttctt gggaagggga atggggttag gaaatggaga tggaaagaaa  33060 

atcagttaga agagggatat tatacagatg atgataacac accatgaact gaggagtatg  33120 

attaaatttt ttgtacccaa ggaataaaaa tggggcttgg gaaattattt aacagtgaat  33180 

gtaaattggg ttggagtaaa aaaaaaacta tgaacataaa aaagaaaaac ttaaaataat  33240 

ccaggtacaa ggacatgagg cttttcttta ggattgtggt aatcgggaat ggaaagtaaa  33300 

ggactagtat aagaaatact gcaaagacgt ggtgtcaaca accagttggg tgaagagatg  33360 

agccaagttt tgaatctggg taactgggaa gatggagata ctattaatta aagaggagta  33420 

gcaaacagaa gataaccaca tgtaactctg acaagatgtg ttgaattcag ctctagatat  33480 

attccattgg aagttccagc atttcactga ggtagttatt cactgttaga gcatttattg  33540 

aggatatact atgtgttagg catcaaagca ggatatatat atatattttg ccaaaattgt  33600 

agcaaaaatt gtatatgtgt atgtatatat cctgctttga tatataagta tacatttata  33660 

tatgaacata tatatgtatt taagttcaga ggtatatgta caggtttgtt atataggtaa  33720 

atttgtgtca tgggtttatt gtcacccagg tattaagcct agtacccatt agttattttt  33780 

cctgatactc tccctcctcc taccctctac cctctggtag accccagtgt ctatagttct  33840 

cctctatggg tccatatgtt ctcatcattt agctcccact tattaagtga gagcatgcag  33900 

tatttgggtt tctattcctg tgttagtttg ctaaggataa cggcctctag ctccatacat  33960 

gttctgcaga gtacatgatc ttgttctttt ttatgactgc atagtattcc atggtgtata  34020 

tgtaccacat tttctttatc cagtgtacca ttgatgggca tttaggttga ttccatgtct  34080 

ttgctattgt gaatagtgct gcagtgaaca tacacatgca tgtgtcttta tgatagaaca  34140 

atttatattt ctttggatat atacctagta atgggattgc tgggttaaat ggtagttctc  34200 

tttttacgtc tttgaggaat tgccacactg ctttccacaa tggttgaact aatttacact  34260 

ctcaccaaca gtgtataaac attccatttt ctccacaacc ttgccaacgt ctgttatttt  34320 

ttgacttttt aatagtagcc attctgactg gcatgagatg gtatctcatt gtggttttga  34380 

ttcgtatttc tctaatgatc aataatattg agcatttttt catatgcttg ttggctgcat  34440 

gtatgtcttc ttttgaagtg tctgttcatg tcatttgccc acttgttaat gggttttttt  34500 

tttcttgtaa ctctgtttaa gttaaagcag gatatttttt attcctaaga tgttttggcc  34560 

ctggtatttc agtctcctcc attttgatcc ttagagtgat ttgattgggt ttcccagaat  34620 

tcgtaaggtt gaaattatac cagtttactg ttgagttaaa aaaaaaaatg acaaaatggt  34680 

taaaacatcc caacaaatta gatctgtaaa atttcaccta agaaaccaga ttttggctgg  34740 

gcgcagtggc tcatgcctct aatcccagca ctttaggagg ccgaggcggg cggatcacca  34800 

ggtcaggagt tcgagaccag cctggccaac atggtgaaac cctgtctcta ctaaaaatac  34860 

aaaacttagc tggacgtgat ggtgcatgcc tgtaatctca gctacttggg aggctgaggc  34920 

aggagaattg ctggaacctg ggaggcggag gtagcagtga gccgagatcg caccactgca  34980 

ctccatcctg cgtgacagag caagacgctg tctcaaaaaa aaaaaaaaaa aaagaaaaag  35040 

aaagaaacca gatttagtaa tagtggccac aaaggaaaac ttaaaatggc agagaatcat  35100 

tgaaatttgc tttgaactaa aaaatgaata ggtgaatcaa atttttgttg taaaatttac  35160 

tctagaagag gcttgatact gttttcagta gtttcagtaa aacaaaattg aaaagggagg  35220 

gaaaaaatag aaactttgtg ccatgtagaa aatcgctctg ggtatccagt cagcttgatg  35280 

tttttattgt tccagaaaat gctgggttct tgcccccact taactgaggt agacttgaat  35340 

ctctcttttt tttttttttt tttttttgag acagagtttt gctcttgttg cccaggctgg  35400 

agttcaatgg cgtgatctcg gctcaccaca acctctgcct tctgggttca agcaattctc  35460 

ctgcctcagc ctcccaagta gctgagacta caggcatgcg ccactgtacc cggctaattt  35520 

tgaattttta gtagagacag ggtttctcca tgttggtcag ggtggtctca aactcccgac  35580 

ctcaggtgat ccacctgcct tggcctccca aagtgctggg attacaggcg taagccactg  35640 

tgcctggcct tgaatctttt aaattagttt tagattatat caatactatg tgagtacatt  35700 

ctcattgtaa tatatttaga ttttataaac aaaataaaag tgaccctgta atcctgtcac  35760 

ttccctctct agaggtaacc accatttgga atatatcctt tcagtttctc tgcttttaca  35820 

aatgtgtgta caaaaaatac gtattgattt gtgaaaattt ggtatttcct atatagtctg  35880 

taagttttga atatataagt attgaatatc tttctgtgtc agttacattg gctcagatgt  35940 

ttgctgggta aaaatggagg ttttataata tccttactag ctaggtactg taaggatggg  36000 

aggagaaagg aacacaggta tgtttgctgc tctcaggagg ctcacagtta gaagaattga  36060 

aaatatataa tcattataat agacaaagtg tcctaataga gatatgtact aggtgtcttc  36120 

ttggtacaga ggaaagatta ctcttggaga aagaagttaa tatgttaggg agtgcttaga  36180 

gatggtaaaa gagattttga atcactttct aagaatattt tgcaggtcag atgtatcctg  36240 

gaatgattaa gtaatatgct cgcttcattc ttctctgtct agtgaaatgt atgtcatctt  36300 

ttggcaataa tcaatctttt tggtgtctta agccaagatt ctaaaagcaa aatctttatc  36360 

atatatgaat attttttaga attttgacag ctttatacag tggcagaaat tacttctgtt  36420 

aatattttta tatttcatct tacagaggat tatgtgaata tattgtttcc cttctttagg  36480 

gaggtggttg actcaatggt tcagcatttt aaagtaacta tatttggaga ccgtagacca  36540 

gtttatgatg gaaaaagaag tctttacacc gccaatccac ttcctgtggc aactacaggg  36600 

gtaagatatg cattcctgta ttggaaaggt atatttttga agtgtctcct tttacacgca  36660 

tttattacca tttttattac agtccatata tatgtgaata tttatcactg attgttttta  36720 

actttttgtt ttgaaataat ttcaaactta aagaaaagtt gcaggaatca tgcagagaac  36780 

tctcatacac cctttatgta gcttcactga ggttctgaac atttccacct ttgttttatt  36840 

ttttttcttt ctctcttgta catacatact tattttttcc tgaaccattc acaagtaggt  36900 

tgcacatacc atgccccatt aatatttatt ttattttatt ttattttatt ttattttgag  36960 

acagggtctc gctttgtcac ctaggttgga gtgcagtagt gtgatctcgg ctcactgcaa  37020 

cctctgcctc ccagattcaa gtgattcttg tacctcagcg tcctgagtag ctgggattac  37080 

aggcacgtgc taccactctt ggctaatttt tttgtgtttg tagtagagat ggggtttcgc  37140 

catgttggcc agactggtct caaacttctg acctcaagta atccacccag ctcaacctcc  37200 

caaagttctg ggattttggg agtaccactg cactctgcca gtatttaata ctttaatgta  37260 

tattcctaag aacaatgata aaaacccttg tacagttatc aagttcatta aatttaacat  37320 

tgatatgata cttttattta atcaacaata caaattccag ttttaccagt ttttccaatg  37380 

atgcccttta gtattatttt tctcctctgt tacagaatcc agtccaggat catgatatag  37440 

ataccatgtc gttctttccc cagccttttt ttatccttca tgacagtaac gtagttgaag  37500 

attatcggta aattattttg tagaatgtcc ttcagtctgg gtttgtctga tacttcccct  37560 

tgattacatt ctggttatgc attattggca ggaatattat ataaccattc tttccttatc  37620 

agtgcatcat atcaggaagc acgcagtatg tatttgttcc attattggtg attattggtg  37680 

atgttaactt tggtcagttg attaaattgg tgtctgccag ttttctccta ttggggtatt  37740 

cttttcctcc ttgtagttaa taagcatctt gtagggagat tctttttgta attgtgataa  37800 

aacatatgta acataaaatt taccgtctta accattttta aggtatattt cagtggtatt  37860 

aagcacattt acattgttat ataattatta ccaccttcca tccccagaat tgtctttatc  37920 

tttcaaaact gaaactccat atccattaaa cagtatccat tgctccctcc cctcagccct  37980 

ggcaaccacc atagtacttt ctgtctctga atttgactat tctaggtacc tcatgtaagt  38040 

gaaatcatag attgtttgtc tttttatgac tggcttattt cacaatttat ccacattgtt  38100 

tcatgtgtta gaatctcctt ttcaaggctg aataatattc cattgtatgt atgtaacaca  38160 

ttttgttaat cccttcatgc atcaatggac accttttggc tattgcaaat aatcctgcta  38220 

tgaacataga tgtaaaagta ttgaactctg ctttcggttc tttggatata tacccagaag  38280 

taaatttgcc aggtcatgtg ataattatta attttctgag aatctgctgt attgttttcc  38340 

agaatggctc catcatttta cattcccacc aacagtgaac aagagttcca aactctcact  38400 

tccatgccaa cacttgtttt ctgttttgtt tttttttttg ttcgttttct aatagtaacc  38460 

atcctaatgg gcgtgagatg atatctcatt gtggttttga tttgcatgtc ccccaacaat  38520 

tagtgatgtt gagtataact ttgtaggctt attggccatt tgtatatctt ctttggagaa  38580 

atctgtggtc aagttgtttg cccatttttt gaactgggtt gtttgttttg ggttttgggc  38640 

agtgagttgt aggagttctt tatttttaga ttttttattt tttttagcta aactgatcaa  38700 

taccattgta ggagttcttt atatatattc tggatattaa cttctgtatt ctggatatta  38760 

actatatata ttctggacat taacttctta tcagatatat aatttgcaaa cattttctta  38820 

catttcacag gttgtctttt cactatgttg tgtccgttga tacacagaag tttttaattt  38880 

tgaaatggga gatactttta aggatcctgt tgctcattgg attttgatta ttcttgcttg  38940 

gcaattgatt attcttgctt gaaaggatta ttactatgta gaagtggtga ttttctaatt  39000 

ctgtcattca ttctccgtat gttcattaat ctgctgtaag ggagtatatt ttcttttact  39060 

ctatttattg atttcactgc ccagattgtc ccagatttgg ccagtgggaa ctcttttaag  39120 

ctgactcctg tgtccttttg aaatgacact ttttggggaa tacaatcctg catcacctaa  39180 

aacaatgggg atatgctctg cgaaatgtgt ccttgggcaa ttttgtcatt gtgctatcat  39240 

cacagtgtat acttacgcaa acctgaatgg tatagcttac tacacacata caccatataa  39300 

tatggtttat tattgctata aacctatata ggatgttact ataccgaata ctgtaggcac  39360 

ttgtaagaca atggtaaata tttgtgtatc taaacgtatc taactataga aaaggtacag  39420 

taaaaataca ttgtaaaaga ttgtttaaat ggtacgcctg tataaggcag cttcattata  39480 

atctaatggg accaccgtgt atatggggtc cattgtggac caaaaatcat tatgtggtgc  39540 

atgactctac ttcattactt tctggcacag gatgttcctg gtttatttta tgttttctct  39600 

gctgcagtcc tgcaactaac catttctctg aggatctctg gtttctttta gttggcaaat  39660 

gcaattttga aatgaaaatc tgggtactgg tatgttcaca gctgctgggg tatatgtgct  39720 

tctaagccct ttcaatggat agaggtagga aatttataaa taagtagata aataaataaa  39780 

acggacaata aaaacatatt acactttgta tggtaaatct aacacatata tataggaaat  39840 

cgtgagttca cacccgattc ttccaattct agtccgtgcc tcatgggatt cttcctttcc  39900 

tcactccatt tcatatttgt atctttcttc tttagttaga ttcctggctc ctcaaaacat  39960 

caccactcct tctcatttgc tcagtcctac agtacatata aaatagtttg tgagaaaaca  40020 

aacctactaa tgattcaagg ctttattttg tatgcaattc ttctaaatcc accctttctc  40080 

tacccctaga attaagacta ttgtcagtat acatactgtg ttcaagagtt acttgaatta  40140 

gagcttcctt tttctttttt ttcaatgtgg ttatgttatt tatttgaaat ttatttgggt  40200 

tcatttgatt ctgtttatga tattctgttt taattttttc cctccctccc tttgtttatt  40260 

tatttattta tttagacagg gtcttgctct gtaacccagg ctggagttca ttggcacact  40320 

cacagctcac tgcagcctca acctctcagg ctcaaacgat cctactgcct cagcctctca  40380 

agcagctagg accacaggtg tgcaccacca cacctggcta atttaatttt ttgtagagac  40440 

taggtcttgc tctgttgcct gggttggttt aaaattccct ggctcaagca gtcctcctgc  40500 

ctcagcgtcc caaagtgctg ggattacagg agtaagccac catacccagc ctaaatatat  40560 

atatatatat tttttattat aaatatataa attataaata atatataaat ttatattata  40620 

aattataaat aatatataaa tttatattat aaattataaa tttataaata tataatatat  40680 

atttatttta tttatttatt ttttttttga gcctcactct gttgcccacg ctggagcaca  40740 

gtggtgtgat cttggctcac tgcaccctct gcctcctgag ttcaaatgat tctcgtgcct  40800 

cagcctcccg agtagctggg attacaggca tgcaccacca cacccagcta attttgtatt  40860 

tttagtagag acagggtttc accatgttgg ccaagctggt cttgaactcc tgacctcaag  40920 

tgatcagcct gcctcagccc cccaaagtgc tgggattaca tgcatgagcc actgcgcctg  40980 

gccttttttt tttctttttt ttaatatgta gaactttaat atgcttccaa atttcaaaag  41040 

tataccaaaa catatactca gaattgttct gtccttattt tttccagtcc attccctccc  41100 

atcctttgaa agtaactagt ttctttgttt ctggttcatg cttcctgtgt ttctttttgc  41160 

agaagtaagc agatatgtga atattttcct cctttcttac acaaaagatg tcataatatt  41220 

tgtaatcttt tgtactttgc ttttgtcact taatagtata gcttggaaat ttattccatg  41280 

gcagtttcaa gagattttcc tcattctttt ttcatagccg catagatgtt ggagcattta  41340 

gggtagtttc cagtattttg caatgacaca taatgctggc acgagtaact atgttattta  41400 

aattttatct acaaaaaaaa atggtatatt ttagtctatt gactttattt ttgccatgtt  41460 

ttctcttaga tatttttata agttaaatct aaaataattg tatttatctt tttcaacatt  41520 

taccagttga ctcttttccc atcaacaggt agatttagac gttactttac ctggggaagg  41580 

tggaaaagat cgacctttca aggtgtcaat caaatttgtc tctcgggtga gttggcacct  41640 

actgcatgaa gtactgacag gacggacctt gcctgagcca ctggaattag acaagccaat  41700 

cagcactaac cctgtccatg ccgttgatgt ggtgctacga catctgccct ccatgaagtg  41760 

ggtgcttctg ctttttttct ctttagattt taaactccca agaatgaatt gtgcaggctt  41820 

cccttggtta aacctttatt tgtcatatat tttgattgtt caactgaaat gttgaacaag  41880 

aatagcatcc atacaaattc attgacagga gtacgttaca gaaaattatc tggcttttgc  41940 

aagtaactat acgtcattag cttagctagt ctcatgaata attttataga aaaatatctc  42000 

accctttctc ttaggatcta aaagtcttaa cagatctatt ttcagatgta tttatttagt  42060 

tatcttgttt taaaagtaat ttcactgttt atacaacaat atcaaattgt gttgaattgc  42120 

tttttttcaa taaccctagg acctcacatg tgtagggtat gctcctgtgt gtgagcgcat  42180 

gtgtacccgt gtatttttta ttgtttggtt gggttttttt tgagacatgg tctcactctg  42240 

tcacccaggc tgtagtgcag tggcacaatc atggttcact gcagcctcaa cctcccaggc  42300 

ctaagcaatc ctcctacctc agccttctga gtagctggga ccacaggtat gcaccatcat  42360 

gcctgactaa ttaaaaaaaa attttttttt tttttttttt ttgtagagat ggaatctccc  42420 

tatgttgccc aggctggttt caaactcctg gactcaagta atcctctcac cttagcctcc  42480 

caaagtgctc ggattacagg tgtgagcccc cacacctgac tcagtatgtt tttttttaaa  42540 

gaaaaatagt atgtcttgca aacacattta tataaatacc tttttgttca ataattattt  42600 

acttgttaac atttttaagg tcggaactgt taacttttta aaacctattt ttaagaaatt  42660 

attttaaata aaatttattc ttatttcaac caacaatttt gagaaaggaa aatttaagta  42720 

gatttttttc catttagagt ggatactttt tgctttctca aatttggaac atgtttagtt  42780 

tcatatattc ataatgataa gcatcattat gttaattgtg ctctagtctc cccttttctg  42840 

cagatttaaa tacttgcatg agaaggaaag gattgaacat gccattttaa tttttgtaga  42900 

tacacacctg tggggcgttc atttttctcc gctccagaag gatatgacca ccctctggga  42960 

gggggcaggg aagtgtggtt tggattccat cagtctgttc ggcctgccat gtggaaaatg  43020 

atgcttaata tcgatggtaa gggaactaaa gccatattct gtattgggtg gtggatttct  43080 

gtatgatgtg tgtacataaa ttttatatat aattatacat actggtgtct cgaagtaata  43140 

tttggacatg tattatgatc tactggagaa acctttatat ttttattaca tttcatttag  43200 

aaagcctgta gaatttacct tggaatgctg ctaaacatga agcaagcaca tgaagacaga  43260 

tttaaaagcc ctgatgatta tctgagcaat cttctattat aactcacttt tgccctttta  43320 

actctaagcc aacattttat tatgaaatat atattttaag aaagataatt ctgttgggca  43380 

tggtgacccc cagatgttat acccactgct ggtcttaatg tgatgctaat tgcattcttg  43440 

tttttaggtg ttttcttaca aaatattttc aagcttatgt aaaaacagag agagtagtat  43500 

tatgaactac cacataggta gccattactc agattgtcag aatttttcta cctttgcgta  43560 

atccgagtac atttcttcct ctacagtagt gtttttaaat ctaattccag acagcatgtt  43620 

attttatccc tattacttca atgtgtacct ctaaaactat ggatattttc ttatagcagc  43680 

aatggcatta tcatatgtag gaaaattata aacaagcatt tatttttacc ctctaatacc  43740 

tgtccacaat cagatttccc tgattgtctg aaatatgcct ttttcttgtt agctggttct  43800 

aatcagaatc caaacaagat ccacacatca catttgatta ttgtgccttt tgccatctag  43860 

tagtcccatt tcctttcctg ttttcttatt tctttatgcc attgacattt tacaaaaact  43920 

gggtcacttg ttctgtagaa tatgttcaaa tctgattttg tctttttgtt ttcttgtgtt  43980 

attaccttgt tcctctatcc cctgtttttt ctgaaaatga aagttagctt agaagtttca  44040 

ttccattctg gttcaaaatg cttaagtgct ttatgtcgtg tcatattagg aaacacagta  44100 

tctagtggtc ccaattttag tgattcaaaa atcagtctct aggttcagag attaatcagt  44160 

agattcagag atctctccat tgtaaatttc ttaattaacc tttgaattgc taatgttctg  44220 

ttcactgatc gttgtggccc aaattattta tttcactagg gattacgaac tggtaatttt  44280 

tctgttattc tttttgcatt aggtggaatt tttctgtgga aaagctcagt gtcctattga  44340 

aaattagtaa atgtttgaaa gctttcttgc tttcgggcac agcaggatat tccttgctca  44400 

tcttatattt cctgcccagt acctgaaatt agacattcct ccaaggatcc ctggatcctt  44460 

ccagattagg gtatagtttc ctcatttttt cagctgcacc taccattgtg taatatatga  44520 

ttgaggaggg gatatattta accagttttc tttagatgta tactagggtt atttttaact  44580 

tttctatttt acatcatttt atgtatatta agataagtct gtaagataca ttcctggcgg  44640 

ttagactgat gagttaaggg caaatgtatt aatatttgta atttgtatca ttgttgccag  44700 

attgcactcc atagagatag taaatatttt gcatcaatga atgagagtac cagtttcctt  44760 

atatctttgc cactagaatc atcaaactct tagattttct tcaatcagat ttgcaagaaa  44820 

cagttttctt gtgtcttctt aatttgtatt tgactacctt ttcacaaata taagggccac  44880 

ttgtgtttct tttttaatga actgttagtt tatatctttt gccctttttt ttctattgga  44940 

tttttcgtct tcttatttac tgagaatgct ttctaaatta aggaagttag ctgttcatct  45000 

gtcatgagtt gcagatattt tacctaggtt gctatttgtc ttttgacctt tggtattgtg  45060 

atgttttttt tgttgttgtt tttgtttttg ccatgcagaa gtttgtttgt atgttggtgt  45120 

gtgcacacat acatatgtat tggtcagtca tttcttttat gacttttaat atctgatagg  45180 

actagtccca tttttctctt ttcagggttt tccagaccat tcttatgtat aagctttaga  45240 

aattccttgt ttagatccag tgagtgggag aggacagatt gttattttta ttgagatcct  45300 

attagattta taaattaagt taggacaaat tggcatattt aaggtgttgt cttttctgtc  45360 

aaagaatata ctatgtcttt ctatttgttt aagattactt tcattttcaa gagatcttaa  45420 

agcttcacat aaattttgca catttctttt tttttttctt tctttctttt cttttttctt  45480 

tctttttttt gagacagagt ttcgctctgg agtacaatgg agtgatctcg gctcacagca  45540 

acctccgcct cccaggttca agcaattctc atgcctcagc ctcccaagca actgtgatta  45600 

caggcatgca ccaccacacc cagctaattt tgtattttta gtagagatgg ggtttcacca  45660 

tgttggtcag gctggtctcg aactcctgat ttcaggtggt ccacccacct cagcctccca  45720 

gagtgctggg attacaggcg tgagccactg cacccaggcc atttcttgtt attccaggat  45780 

attttctcct ttttgttgct attaaatggg tttatagata ctaactggta attgcttata  45840 

tatattcagg cttttgattt ctgtatactt tctctctttc tgtgttattg aattccatta  45900 

ttgtttgtgg tattttttca agcgatttta ttggggtttc taggttataa tcatcacctg  45960 

caactagtga taagtttacc tcttcctttg gatttttata cctctaattt tttttatcag  46020 

attatataga ctaattagac agggtaggat taaatagtag tgattaatgt gcgtcctttt  46080 

tctttcttgc tctagaagca ttaagcattg tatgtataca ttgtcatatt aaggaatatc  46140 

tgtttcttat taagtacgtt tatcaagagt atgtgttaaa ttttgtcaga tgccttttca  46200 

gcatctatgg agctgatgat gtgatatttc tcttattttt aacaaacatt gaaccaaacc  46260 

aggactccta gattctttta attgatgctg gattctgttt gctaatactt tccttttata  46320 

aattaacatg cagaagtcat attaatctgc agccttcctt ttttgtacaa tctttgtcaa  46380 

gttttggtat tatttcctaa aaaattcaga agttttccat tttctaaaat gtataacagt  46440 

tttaaaatag tattgatatt atcagctctt gtatgatttc gtagaattcc cctataaaac  46500 

cttgtgacct gccgtttttt gtttggtttg gtttggtttg ctaggtagct gttttaaaac  46560 

ttccctcatt tattttgtga aaatcagtct aataatttat cgtacaatta aaaataacta  46620 

aaaatataat tggattgttg gtaacataaa gaaaggataa atgcttgagg taatggatac  46680 

cccatttacc ctgatctgat tattatgcat tatatgcttg tatcaaaagc tcgtgtaacc  46740 

catagatata tacatctagt atgtacccat aaaaattttt ttttaattaa aaaaaaaagt  46800 

ctgttcaggc tgtttaggtt cacttttggt agctcacatt ttactggaaa attattttat  46860 

tcatatgtaa tttaattata cagagtttta caaagtagtt tctatcgtta ttatgatttt  46920 

tttttttttt tttttgagac agggtcttgc tctgtcaccc aggctggagt gcagtggtgt  46980 

aatcttggct cactgcaacc tccacctccc agggtcaagc gatcttccca ctacagcctc  47040 

ctgagcagct gggactacag acacatgtta ccacacctgg ctaatttttg tattttttgt  47100 

agagacaaga tttcaccatg ttgcccaggc tggtctcaaa ctcctggtct caagagatct  47160 

gcctgccttg gcctcccaaa gtgctgggat tacaggcatg tgccaccgtg cccagctagt  47220 

ttctattagt ttttgaaatt ctgtgtattt ttgtggtttt cccagtctgt tattttgcat  47280 

atgtatgctt tgttcttttt actttttttt caggtagtga aattcagtgg tatttatttt  47340 

tctccatctt tttcaagctt tcaacaataa gcatctatta cttcttatca aaaaactaaa  47400 

aaaaagacgg tatggcatca taaatattta ttttagaaaa caaaatgtat ttattgagtg  47460 

ctttctgatt aagaacaaag tatagttaat gaatgctgat tgtttaatta agtagtttaa  47520 

tccttaacct tttttcctat gccctgactt cttttttggt aacatagtct tcccaattaa  47580 

tgaattactg aaacctataa taaagaatat tttctattat tctagctcag gtgtatattt  47640 

agtacttaaa cttaaatact tgaatcaatg aaataaaatc ttgatgaact ctttctagag  47700 

atgtaaggta cccaaatttc ttgacacaat tttttttgag ttttgctctt gtcacccagg  47760 

ctggagtgta gtggctcgat ctcgactcac tgcaacctcc gcctccctgg ttcaagcgat  47820 

tgtcctgcct cagcctccca agtagctggg attacaggtg catgccacga cacccagcta  47880 

atttttttgt atttttagta gagatggggt ttcaccatgt tggtcaggct ggtctcgaac  47940 

tcctgacctc aggtgatccg cctccctccg ccttcccaag tgctgggatt acaggcgtga  48000 

gccaccgcat ctggcctgaa aacaattttt ttttttatta acgttaaact cactagaaaa  48060 

ctctcaagaa ttgtgttgaa gatcatttga aaatatatct gccaacttcc tcttccttcc  48120 

tgaagtgtgt ttacagacag agcaagttac aacagtctta ctattctttg aggatagagc  48180 

agcttcctgg ggattctgga ggctcagttt tctggtctgt tattaggaca caatactgat  48240 

gttgaggaaa gtaaggcctt gctgacaatg ggaattattc ttaaaagtta tttttctatc  48300 

tattttagct agattagtaa catgtacttt cattttgttg gtggaaatat ttaaaacaat  48360 

tatttttctg gtgatcactg ttttagccgt attacaaagc ttctaatatg tagtattttt  48420 

attatattct agaaactaga aatacataat attattttct agaaactcca caaatttcat  48480 

ttgtatttcc tctgtgcttg aaatattgtt tgagagactt ttcaaatttt cagattgaag  48540 

atctttttgt tttctggatt tgttgtgaat ttctagtttc attgtgttgt taaaaaatgt  48600 

tgtttgtggc tgggcgcggt ggctcatgcc tgtaatccca gcactttggg aggccgaggc  48660 

gggcggatca cgaggtcagg agattgagac catcctggct aacacggtga aaccccatct  48720 

ctactaaaaa tacaaaaaat tagccgggcg tggtggcggg catctgtagt cccagctact  48780 

tgggaggctg aggcaggaga atggcgtgaa cccaggaggc ggagcttgca gtgagccgag  48840 

atcgcgccgc tgcaccccag ccttgggaca gaatgagact ccttctcaga aaaaaaaaaa  48900 

tgtggtttgt atttttcctt ttagagtttc tagaggtatt ttttgtagcc caatatacgg  48960 

tcaatttttg tgatagttct atggctatat gaaaataaga tatattcata tattagttta  49020 

gagtgaaata tccatcagag ctaccagttt gattatgttg cttatgtcat ttatttcctt  49080 

agttttgttt tttgttctct cagactagga taaataaatt tcctattatt aatatctttc  49140 

tgtttcttct tttatctcct gtaatttcca ttttctgaat gttgctactg tattaggagc  49200 

atatatattc atatctgttt tcgttatgaa ttataacctt tatataagtg actttctttt  49260 

tgtacttttt gaccaaaatt ctacattatc taataaaaag attgcacttc atgcttttgt  49320 

gaactttatc ctatccttta actttttttt tcaggtatat cttgatgaca gcatagaatg  49380 

gtttgctttg tgggtcagtt taaagctttt tttctgtttg gtggatgaat taagccagat  49440 

atagatagga aggacatatc tttctgtcaa gtcacaacca ttggtcatgg ttttgtaaaa  49500 

ttattttatg ccatttttta catttgtata tattttgaaa ctttgagtgt tgtgttttct  49560 

gtgcttttta aatggtagtc ctcatcttag gaagattttt ccccccagtg gttatcttta  49620 

tacttatacc ttcatatgat acctatcttc ctctgtttta aagcagtctt ttgtttccct  49680 

taattgagta acaattacat tagctttatt ctcttccctt ctttctacta gttttagcca  49740 

atatagtatt attttattgc tctttataat tttattctgt catgttgctt aagtttttac  49800 

tgattgactt tcaactttga ctcctacctg ttgcacatga ggtgcagtca ttgagcttat  49860 

tctacttttc atatattcta ctcttaacat ccatttgtat atattcattg atttgaattc  49920 

ctacattctt agaccatgta acagtttcat tccatttgtt ttcaatctta aatctgcaat  49980 

taaatgtatt gttgctcact gccagtcctt ttgctgaaat ttttctggtc atttgttggt  50040 

ttcagtttgt cctcaagttg tttcttcaag aaatgctcat atgaataagg cctgagttat  50100 

ctgtagcctt attcctgaag gactgtttgg ctagatgtgg aattgttggc tcacactttt  50160 

tccttgagta ccttgtaggt atttttccac tgtcttctgg cattgactgt tcaatagaga  50220 

agtatgatgc cagcttgatt ttatttttct tagaaggagt gtgctttttt gtgtgtgatt  50280 

gctgaaagta tttcttccaa ataccaaata atttagaaat tattttatta agtgacatca  50340 

gtaaaattac tagatgtttt cttagttgac cattttgggt cagttttata tccatcattt  50400 

tatttacttt taaaaaattt ctatcctaca tgcttcttac tgtgcctttg gtgttgtata  50460 

tttttaccat gtgctcattg cattttagtc ttcatctttt taattcttaa aattcttttt  50520 

ctcccatttc ttttctgagt tctgccatgc ttgtttcact acaactcctg ttgactggtt  50580 

agttgctcct tgagtttcta aatttctcct ctgaactttt tcttcataac tgcattagga  50640 

atttttcagt gtgagtaaaa agtagggttt taattttcct ctgctttgtg atgatattgt  50700 

ctgttgagtt ttctttgtca gaaatgtcgc ggtgcctttt tacatttttt tctatggtat  50760 

tattgtatgt atacttacca cttttttgtt gcttatattg gcatgagatg agtttcccaa  50820 

accatctgtt agaagggact taagggtgtt aggaacatta ggaacacctt cggagcaaga  50880 

tagttttcca ggtttctgtg ctcaaggcct ctctcctcca ttgttctggt ggactctttc  50940 

ttcaaaatgc agccacatct cctatgcctc tcagtaactt aaggggttta agtaatatga  51000 

actaccagcc atgagttccc caggtcctga ctagttctgc taccaaggga tgcacctcct  51060 

accctttaaa ttgcctgcct caaatgttaa caattaaaga atttgtgaca ggtatacagg  51120 

agttttttgt actattctta taacttttct gtaagttcga aactacttca aaagaagaaa  51180 

ttacaaaaga gcatgcctca cttgtaaaag ggtggtcctt tctgagatct gtcacttcca  51240 

aaccaccctc cacttattgt tctgccactt tctacacctc ctttccttac ctccttctga  51300 

gaatccccca tttaatctca gttctaaaca ttgtagttcc cgcttggtat agattctttt  51360 

ctttctggga gtaaatatgt gctattcccc caccagattc ctttatactt cttgtcattc  51420 

tctcatgctc agatgtggct tcttttagtc tcaagtactt tgggtcatat ttacttagaa  51480 

gttggcattt ttaggttttt attatcccct agtttcacta aagatatatg gtattttttg  51540 

tttttaacat tgtttttgtt gctctgtaca ggttctagga gaaagatggg aaaatttgga  51600 

actaaattgc tgttatgttc ctactagaac ttgaagtcca gctttgaaaa ttattaagaa  51660 

ataatttcta ggctgggtgt ggtagctcac acctgtaatc ctagcacttt gggaggccaa  51720 

ggtgggagga tcacttgagc cttggagttt gagaccagcc tgggcaacat agtgagaccc  51780 

catctctatt aaaaaataaa gaaatgattt ctaaataacc ccttgtttaa agaaatcaca  51840 

gagaaaattt tgaactgaag gacaatgaat acaatacata tcagaactgg tatgatcagc  51900 

taaagcaatg cttagagaga atttaaaact tgaaatgccg attttaaaag aaaaaagcat  51960 

cagtgacata agcattcatt ctcaacaagt tagaaaaatc acagaaaatt aaatgcaaag  52020 

agaatagaaa gaaataaaag ataaaaacaa atcaatgaaa taggaaaact tctctctatc  52080 

ctttagatag ggatacttca aaggttttta agaaggatag tgacatgatc atatttgttt  52140 

tccagaaaga gacctctggc agcagtgtgg agaatagata gaggagaaaa aactaatctg  52200 

agaagccagt taggaggctt ttcaatcact agttcaggta agagatggtg atggtctaat  52260 

gtgggatgga gaggaaggat taagctgaaa aaataggttt aagaaccatg tccagaaaaa  52320 

aaaaactttg ggtgtagtac tggtacatgg aacggattgg aaaaaaatag accagagctt  52380 

tactagattt ttgaaagaat tgtttttgca aataaactac aagcctggca tatcagtcaa  52440 

ggttcagaac ctagagaagc agaaccagta cgaagtatag agagagagtt tatgcaattg  52500 

taggggctag ctaggcaagt ctgaaatttt gggggcaggc tgtcaggaag ggcagggaaa  52560 

ttcaggcatg ggctgaagca gttatctata agtggaattt cttgctctca gggaagcttc  52620 

agccctactt ttaagacctt tcacctaatt gaatcaggcc catccacatt attcaggata  52680 

atctccatta cttaaagtca acagattatg gattttaatt acatctacaa aataccttca  52740 

tagcaacacc tagattagtg tttgattaaa caaatggcag ctggtagcct agcaagttaa  52800 

cacattaaaa acaacacctg ccatgatggc ttacacttgt aatcccagca ctttgggagg  52860 

ccaaagtggg aggatcactt gagattagga gtttgcgatc aggctgaaca acatagtgag  52920 

acctgatctc taccaaaaaa aaaaaaaaaa aaaagaaaaa gaaaaaaatt agctaggtgt  52980 

ggtgcgtact tgtagtccca gctgctagag aggctgagat gggagggtgg cttgagccca  53040 

ggatatcaag gctgtggtga gccatgattg tgccactgca ttccagcagt gacaaagcaa  53100 

ggccccatct caaaaataaa taaataaaaa gaaaaacaac cctccacacc tggtctgaaa  53160 

ttttctgtga ttattcagcc ctcgaaacaa ctttcaggta cagtgactgc cataatgtaa  53220 

actggctccc aagaaggtca tactctccaa tgtacattca gagtactgac tctgagtttt  53280 

ctgccaggta tgaatggtgg tactgtcaac tgaatatgga ggtagatctg ctattgctgg  53340 

ttagttggca gtatacacca tgtatcaatg ttaacatgtc caaagcttga ggattctatg  53400 

gaacatatag atagacatat ctagtgtata tttagaaatt taggtatgaa aatctataat  53460 

ggtgggagct gaaagtaaga gtgttgggac tcttcagtat gtaaatccat atttgaaact  53520 

atagaagtgg aaaaactctt taggaatagt atttagattg aaacaggaaa gaggaggata  53580 

aagccgtcga ggaatactag catttaagaa aaaaagaact agtgagcaag taatgattat  53640 

acaaggcaat atgagacacc aaatatgatg tcaaaaaagc caagagggga aacatatcca  53700 

aaaaataaat gagctgggca caggggctca cgcctgtagt cccagctact tgggaggcta  53760 

aggcaggagg atagcctaag ccccaggagt tgcaggctgc agtgagctgt aattgagcca  53820 

ctgtactcca gcctgggcaa cagagtgaga cccctatctc taaaaaaaga aacaaaaagt  53880 

agatgatttc acagttaaac aatgagagct ttttcaataa aatcaagaga caaggatatc  53940 

agtgctatga tttttagtca ctattgtgtt tgctaacttc tgttcttctt acaggtttca  54000 

gtctacatgt tacttccttg agaagcagtg tttgacaccc ttctccccca atccagccat  54060 

cccccaagtc tgagttaggt atttctcttc tgtattccca tagcacagtg taattcccct  54120 

ataatagcat gtatcacctt gaattatggg tgtttattgt tctgtctctc ctgttagaac  54180 

gaaagctcca tgaagggatt gtcattttat tcaccagtgt accctctatg cccagcacaa  54240 

cttttggtca tattaaacaa agaatgaata aataaatcca agagcatagg aggaggagca  54300 

tccaaatgag cctgaaaaat tagagaaata tttgtagtag tatgtgatat cttagctgag  54360 

cttaacaagt ataatgagat caagagtttg gattgaaaat gaggtactca ggaataaacg  54420 

atttctgagg tctctaagat attataaaac tttattgaaa gatctaagaa aatttaatga  54480 

aacacattgt ccttattaat ctataaatat agttttaatt aaaattccaa tagggggcca  54540 

ggtacggtgg gtatgccagt atttccagca cattgggagg ccaaggtggg aggattgctt  54600 

gagcctggga gttctgacca acatggtgaa accctattgc taaaaaaaga caaaaaaatt  54660 

agccaggcgt agaggtgtgt gactgtagtc ccagctactc aagaggctca gttgggagaa  54720 

tcgcttgagc ccagaagtcg aggctgcagt gaactgtgat ctcaccactg tactccagcc  54780 

tgggcaacag aattagaacc tgtctcaaaa aacaaataaa ataaaattcc aatagggtat  54840 

agtataacac ttgataagtc gatattaaga tttatatgga agaataagtg actaagaaaa  54900 

accaatagaa ttttaaagaa aaataaagca gaaattgccc tacttcctat aaaactgtaa  54960 

cagttatacc acatggcttc aggtgcagga acaggcagat taatgaagca gagtctagaa  55020 

acgagccaca tatgtgttta tggaaactgt aaatatctga tgtagtgttt cagatcagta  55080 

gggaaagagt agaatattta ataaattgtg tttacacagt ttaactttaa aaaaattaga  55140 

tccatcttac attagacaca aaatttattt ctaggtgaat tatatcccaa atatgaaaag  55200 

caaatcttca aaattctttt aggataaaaa tgagagaatg ttcctaacac caaacaaagt  55260 

acaaagtata aactgcaaag gaaaatactg ataaacttga ccaaaattta aaacttgtgt  55320 

atcgcaaaag aaacaataaa gttaaaaaca ttagaaaatt tgtaactcat ataactgaga  55380 

actttacaaa atataagaac agataaattg aaaaataggt agttctcaaa ataggaaatg  55440 

catatagcca gtaaacacat gaaaagattc tcattcatta ataatcaaga acttgcaagt  55500 

gaaatcagtg ttaccatttt ctacgcatca gatttgtaaa attaaaaagc cttatgattt  55560 

gcaaaaagtg caaggtgaaa agaaaaatct tatgaaatac caaatgttgg tgaggatgaa  55620 

gtaaaaggaa ctctcacaca ttgtttgtag tagtaccatt tggtacaact accccggaga  55680 

gcaattctca actagaagag atgaagtaaa gatgaaattg cataacttaa aacccataaa  55740 

gagatatctt gcatgtgtgc ttgaaacatt atatgtaata gcagaaaatt ggaaacagcc  55800 

taaattcctg tcagtagcag aatgaataaa cagcacgtaa atagttacat aatattgtgg  55860 

tgtactacat aacagttaaa taaatgaacc agatctatat gtatcaatgt gaattattaa  55920 

aataatgttg tacccagaca tcatggctca tgcctataat cccagcactt tgggaggcag  55980 

aggccttcgg atcatatgag gccaggagtt caagaccagc ctggtccaca tggtaaaacc  56040 

ccatctctac gtaaaataca aacattagcc aggtgtggta gtgcacgtct ataatcccag  56100 

ctacttgggg gttgaggcat gagaatcact tgaacccagg aggtggaggt tgcagtgagc  56160 

tgagatcaca cctctgtact ccagtctagg caacagactg agactctgcc tcagaaaaga  56220 

aaaaagaaaa aaaaaatggg ctgggcctag tggctcagac ctgtaatccc agcactttgg  56280 

gaggccaagg tgggtggatc acttgaggtc aggagttcga gaccagcctg gccaacatgg  56340 

cttaaccctg tctctactaa acatacagaa attaaccagg cgtgatggtg cacatctgta  56400 

atcccagcta cttaggaggc tgaggcagga gaatcacttg aacccagaag gcagaagttg  56460 

cagtgagctg agattgcacc actgtattcc agcctgggcg acagagtaag actccgtctc  56520 

aaaaaaaaaa aaaggaaaga aaatgttggg ggtgagtaaa cagcaaaagg ggctaggcac  56580 

ggtggctcat gcctgtaacc ctagcacttc gggaggccaa ggcaggtgga tcacttgagg  56640 

tcaggagttc aagactagct tggccatcat ggtgaaaccc catctctact aaaaatataa  56700 

aaatcagcca gacgtggtgg cacgcacctg tagtcccagc tactcgggag gctgaggcag  56760 

gagaatcagt tgaacccagg aggcagaggt tgcagcgagc cgagatcatg ccactgcgct  56820 

ccagcctggg cgacagaaca agattctgtc tcagaaaaaa aaaaaaaatt agcctggcat  56880 

ggtggcgtgt gcctgtaatc ccagctacta gggaggctga ggcaggagaa tttcttgaac  56940 

ccaggagacg gaggttgcag tgagccgaga tcacgccact gcactccagc ctgggcaaca  57000 

gagtaagact ctgtttcaaa aaaaaagcaa aaggatatgt tattatttat ataaacttag  57060 

aacaaaagta tgtactaggt acatacaaat aaagtaaaat tataaaacag atgggacaaa  57120 

tacacaccaa tttcaagatt ttggatcctt ttaggaagaa aaaagagaaa tggaataagg  57180 

tgcctgggtt gggagaagag atagaccaaa aaaatttaag aaaaatgtga gagtatgttt  57240 

atgtgagcaa agtataacgt gccattggga ggcaaaaaaa taagattgat taaaaaaaaa  57300 

aaaagaccta tgggccaggc gtggtagctc acacctgtaa tcccagcact ttggaaggcc  57360 

taggtgggca gatcacgagg tcaggagttc gagaccagcc tgaccaacat ggtgaaaccc  57420 

cgtctctact aaaaatacaa aaatcagctg ggcatggtgg cgcacacctg taatcccagc  57480 

tactcaggag gctaaggcag gagaatcgct tgaacccggg aggcggaggt tgcagtgagc  57540 

cgagatcttg ccactgtact ccagcctggg tgacagagca agactctgtc tcaaagaaga  57600 

aaaaaaagaa aaagacctat ggtaacttaa tgaaatggaa ataaagccta acatttgaag  57660 

ttggtttatt ttctccccag ctaatgtatt caggtatgat taacaagtaa aagttacatg  57720 

tatttgaggt atacagtgtg atttttgata atacatatgc attgtgaaat gattaccaca  57780 

atcaaggtaa tgaatataac aatcacctca taggtatgtg agagacataa gaacatgaaa  57840 

tttactctca gcgtatttca agtatacaat aataattata gtcaccatgc agtacattag  57900 

gtctccagaa cttactcatc ttataactga aagtttctat gctttgacca acatctcacc  57960 

atttgcctca gccctcagcc ctgggtaact accattctaa cctctgtttc tgtgagttga  58020 

gctttcttag attccacatg tgagatcata cagtatttgt ctttctgtgt cttgcttatt  58080 

ttatttaaca taatatcctc caggttcatc catgttgtca caaatgacaa gacttccttc  58140 

ttttaaaggc taaataatat tccattttat gtatatacca cattcttttt atccatttgt  58200 

ctgtcgatgg tcgcttaggt tgtttccata tcttggctgt tgtgaataat gctgcagtga  58260 

acatgggagt gcaggggtct ccttgagata gtgattttat ttactttgca tgtagtccct  58320 

gaagtgggat tgctagatca tgtagtagtt ctatttttaa ttttttgagg aacctccata  58380 

ctgttttcca taaaggctgc aacaagggtt tattaattgc caataaaatg ctatgaaaaa  58440 

taatgagaaa tattgcactg accatcttac ttgcttacat ttcctttttg cttttgcgtg  58500 

attttgattt tgcaagcctt gtacgtggta tatgcactga actaaacagc ctttattgaa  58560 

cttgaaatca gctggagaag actggtaatt gagcactata ataagtactg taaaggaaaa  58620 

taccaagtgc aatggaagca taaaagggag ggatccattg tagtctcact ggttgaggga  58680 

tgtttccctc aggaaatgac agatgggagc taggcgaaat tggtgatgga aataagcatg  58740 

gaagagtact ctaagaaagg gagcaattct ctctaattgt gtgattggtc ttgagaatga  58800 

ttgttctatt ggcatttaat agcctaactt tcaactgtgt aattaaactt gctgtatttt  58860 

accaatctaa gactcaaaat tttttgttta catttcaaca tctctgaaat tgggagatat  58920 

cttacaattg atggtttgtc acagttcagt tggcaggttt ctttttaaag aatacataaa  58980 

atactggtgc agcttaccat caatggcatc ttagatttga tgaaatgaag aatatttctt  59040 

tagcttgttt tgaggccagc ccatttgcaa cttgcatttt attattgtaa ttcacagatt  59100 

ttaagaccat catagtggct gggcatggta gcttacacct gtaatcccag catttttggg  59160 

aggttgaggt gggtgtattg cttgagtcca ggagtttgag accagcctgg gcaagatggt  59220 

gaaaccctgt ctctacaaaa aatataaaaa ttagccaggc gtgatagcat gagcttgcaa  59280 

tcccggccac tcaggaggtt gaggtgggag aatcacttga gccgggaggt ggaggttcca  59340 

gtgagccatg atctcaccac tatactccag cctgggtgac agaacaagac cctgtctcaa  59400 

aaaaaaaata aaaagaccat catagtgaat ctgatgtttg ttagttatat ctcccttaag  59460 

atgttattta cctcttatta tgtaccagat agaatgctaa gcattttata ttaattatta  59520 

atactacagt gttgcatgta aattccacca cagttgtata agttggtagt atcatcaact  59580 

gaagtttaga gacagaaagt cacatagttt atatttaaag cgggagaagt tcaactcttc  59640 

tgactccagt gcttatacct ttaacatagc tctgtactgc atcccttaag aagcaagatc  59700 

cctggcaggc aaatctcaga tcttagacac attagttaaa tttatttttg tggccaggca  59760 

cggtggctca cgcctgtaat cccagcactt tgggaggccg aggggggtgg atcacgaggt  59820 

caggagatca agaccatcct ggctaacaca gtgaaacccc gtctctacta aaaatacaaa  59880 

aaattagctg ggcgtggtgg caggcacctg tagtcccagc tactcgggag gctgaggcag  59940 

gagaatggcg tgaacccggg aggcggagct tgcagtgagc caagattgca ccactgcatt  60000 

ccagtctggg cgacagagac tccatctcaa aaacaaaaaa ttttattttt gtttactgtt  60060 

acttttcagt aaaatgtagc tgtccgtaaa acattcacta tcccattttg cttttagtaa  60120 

aaagtaggca gaatatgtaa atggttgtag aatttaataa ttttatttct gcaaagtagt  60180 

tagaagttca cactgctgct tttgcaagga aaacatttct agtaaataaa aatttctagt  60240 

aaataaaaaa ttctagtaaa taatttatta atcacagtat tagtgttgct tacttcatgt  60300 

atttgtcttg agttcaggta taagattgct aagattgaga aataatttga ttttataata  60360 

ttcaaattag tcctttcaga ggtagatcaa agcagaactt ttctttcggg tggaatgaga  60420 

gttatcagct gattcaggca tctgggcaag aacttttagc aacatgagtt caaacaagac  60480 

caactaaaga tatctggatc aggcttaccc aggcgggcta tcttcacatt agaaaaacag  60540 

tataaggctg ggcacggtgg ctcacgcctg taattctacc acttatggga ggccgaggtg  60600 

ggcggattgc ctgagctcag gagttcaaga ccagcctggc caacacagtg aaaccctgtc  60660 

tctactaaaa tacaaaaaat tagccgggca tggtggtgtg catctgtagt cccagctact  60720 

cgggaggctg agacaggaga acccaggagg cagaggttgc agtgagccaa gatcgcgcca  60780 

ctgcacccag cttgggcgac agagtgagac tccatctcca aaaacaaaaa cagtaatggc  60840 

tgcaggaatc tcagtgacag tcttcatgag atctgtctct tgattctcac tgtttcagtc  60900 

tggttgagtt atgccctttg tgtttggtgc gcagctgtct tcttgagatc acacttcact  60960 

gttgccctgg gaattccttt tgtctttgtt ctataatctt atttcttttt aaaaaatttt  61020 

cagaatcttc atgagaatag ggtacctggg gagcaaattt tatatatata tatatataaa  61080 

atatataata tatgtatata ttagaaaatg tatttatcaa caaacttaaa atgatagttt  61140 

agctctttct gtggtggaaa taatttttct tcagaaattc gaaagcatca ctccattttt  61200 

aaaatagctg tattgacgtt taatttacat accataaaat tcacacgttt tatttcctaa  61260 

gtgttatctt tcatagcatg ctattcttgt ttcacagatg cagtatcctc tcttagctct  61320 

ctgagcataa tttattttgg agttcttcct gtacatgctt atgcttccct caaattcctt  61380 

tttgtttgtt ttgatctctg tcttccattt tggaggcgtt catccaatat ctagtattct  61440 

tgattactgt ctattcagtg ttaatctaaa aacactgaat gctctgaagg catggatagg  61500 

gtttgttgac tctgagcctc atcatagggt gatttcagag ggcttaggtt ggggaatcta  61560 

caatgttagg atccttaggt ctcttctctt ggctggtcag gttgtccaaa ggtgagtctt  61620 

ctaaactcct gcctaaagga tagcagtgtg gttgcctgca ttctggaagc ctagttggga  61680 

gttctagctg ggggaacttc tgtattcagc atttaatatg ttaaagtcat ttaatctctt  61740 

gtttttggta cagtcttgtg ctctcaactg tgtctggcat ccttcttcca gggagcctct  61800 

gttgtatctc ttccagttag tatgcctgca gatctgtgca aggatgaaca agaggcagct  61860 

gttcatcaat gtgagctaga cagaggatat aggactctac ctgcttctca gactgctttt  61920 

ctctttattt ttctgcatca ctcccatcct tttatcacca acttgctcac ttgcttttca  61980 

tctttcagaa tgttgatata tcccctgttc tgttctcctt ctaggtttgt accttaaatt  62040 

tttttttaaa ttcatagtta cagtggagtt tgagaaagga atgaaatgaa gaatgataat  62100 

agatgctcat tgttaatctg ccatcttaac ccagaatctg ttattaaagg gcaggggctt  62160 

tgtctggttt atctctaaat ttcaacccat aaaggaatct gtgacatagc atatacttaa  62220 

taaatgtttg gatggttaag tcttatttta tgtctgtgtt agttatctac cactgcatat  62280 

caaattattc caaaacgtag tgactcaaaa caataaacta tctcacacat tttctatgag  62340 

ttaggagtga cttcgatggt tctagttcat gaggctgcat tcatctcaag tccttacagg  62400 

gcctgggggg attcacttcc agtaggactc acttaattgg taacaactta gttctggagg  62460 

cctcagttcc ttgccatgtg gacctctcta taaggctggg taagtatcct cacaacattg  62520 

tggctggctt cctccagagc aggaattcat gagagagcaa ggcagaggat ataataacat  62580 

taagacctag cattgaaagt tacattcttt tatttttata ataccctatt ggttactcag  62640 

attacttaat gttcagtatg ggaagggact gtacaaagct gtgaatccca tatgtcaaga  62700 

ctcattgggg accatctcaa aggctggcta ccacagtttc tgacttaagc tagaaataga  62760 

agagcatatt aaatccaaag taagcagaaa gtaagaaata ataaagatta gagcaaaatt  62820 

taattaaaaa actgtacaga atatcaatga agccaactgt tggttattta aaaaaaataa  62880 

gtaggattaa taaactccta gcaagactaa tcaggaaatt aggaaaaagc agattaccag  62940 

tatcaggaat gaagtgaggg tatcactaaa aattcttcag aattgaaaga ttaataaggg  63000 

aatggtatga acaactttat gccaattaat ttgataggtg aaacaaattc cttgacaagc  63060 

cacaccttta ccaaaattga ctcgaaaaag aagcctgaat agccctatat caaagaaatt  63120 

gaattcacaa ttcctcctca caaaactcca gtcccaaatg atttcactag tgagtttttt  63180 

ctataatgta aggaaaaata acatcaatct ttcacaaatt ctttcagaaa atagaaaagg  63240 

cttccccaac caccaccccc tgcttttttt tttttttttt tttttttttg gagacagagt  63300 

cttgctctgt cgcccaggct ggagtgcaat ggtgagatct ctgctcactg caacctccac  63360 

ctctcaggtt caagccattg tcctgcctca gcctcccaag tagctgggtc tacaggcatg  63420 

caccaccatg cccggctaat ttttgttttt agtagagaca gggtttcacc atgttggcca  63480 

ggcgtgtctc aaactcctga ccttatgatc tgcccacctc aacctcccaa agtgctggga  63540 

ttacatgcgt gagccactgc gcccagattt tttttttttt tttttttttt tttgagtcag  63600 

gttcttactc tgtcacccag gctggaatgc agtagtgtga tcatggctca ctgcagcctc  63660 

aacctcccga gctatgctgc tcaggctggt cttgaactcc tgggctcaag caattctccc  63720 

atctgggcct cccaaaacac tgggattata gccataagcc accatgcccg gccccagttc  63780 

attttttgag gctggtaaac ctggtactaa cccctgacaa agacaatata atcctctcaa  63840 

caggaaaatt gacacatttt aaacattctc atgataaaaa tttacaacaa actagcaata  63900 

aaaggaaatt tcttcagcta attaaaaaca cttagaaaag catacaggca tcatcatact  63960 

tctgtggtga aaagattgta cacttttgcc ctaaattcaa gaacaaggca aggatgcttg  64020 

ctctcattat ttggtaatca tactggaggt cccaggcagt ggcaaagcaa gaaaaggaaa  64080 

taaaaggcat aatttgtaaa ggaagaaata aaactctgtt tgtagaagac ataatactct  64140 

acattaaaga atctaccaaa acaaacccca ttaaaattat tagaattagt acatgaattt  64200 

agtgaggtca caggatgcta actgcataaa caaataatac cagcattcaa caattgaaat  64260 

gaaaaaaaat ttaagtgcca ttcataacat aaaacataat ttttaggaat aaatataaag  64320 

atgtgcatgg cccccacgct gaaagctaca aagcattact aagaaagaca aggaaggtaa  64380 

agaggtgttc ttggaccaga agtctcaaat tgttaagaat ttcattctcc ccaaattgat  64440 

ctataaactc aatacaatag aaatcccatc aggcttactt tgggaggcca aggtgggtgg  64500 

attgcctgag ctcaggagtt tgcgaccagc ctgggcaaca cggtgaaacc ctatctctac  64560 

taaaatacaa aaaaaattag ccgggcatgg tggcgtgtgc ctgtggtccc ggctactcgg  64620 

gaggctgagg caggagaagt gcttgaaccc gggaagcaga ggttgcagtg agccgaggta  64680 

tcaccactgc actccagcct gggcaacaga gcaagacact gtctaaaaaa aaaaatatat  64740 

atatatatat atatatatat attatataaa attgtcaagc tgattctaag atttatatgc  64800 

tggtacaaag aacttaacat ttctattttg aagagccaaa aaatctttta aagaagaacg  64860 

aagttggtgg atttatacta cctgtgttca agacgtgcta taaaactact gaaatcaaaa  64920 

cagtgatact ggggtaaaga ttgtcaggtt acagaatagc taccagaata gacccactaa  64980 

tgtagctggt tgatttttgg caaagggccc aacataatag aatgccaaaa aggttagtct  65040 

tctcagtaaa tgatgtaaca actgggtatt tgtattaaaa aaattatcct ctacttaaca  65100 

gcacacagaa aatttaattc agagtttatc ccaggataaa acattaaaac tggtaaattt  65160 

ccaagacaaa atggggaaaa tattcatgat cttggacgag gcaaagattt ttttcttctt  65220 

tcgagacagg atctccctat cacccggact ggagtgcagt ggcttgaact tggctcactg  65280 

caacctctgc ctcccgagtc caagtgattc ccccacctca gcctcctgag tagctgggac  65340 

cacaggtgca tgccaccacg cctgggtaat ttttgtagtt ttagtagaga cgaggtttta  65400 

ccatgttggc caggctggtc tcgaactccc tgacctcaag tgatgcaccc acctaggcct  65460 

cccaaagtgc tgggattaca ggcataagcc actgcacccg gctaggattt gttaataaat  65520 

tgaaaaccat tgcaattaaa agcttctcct tttgagaaca ccattaagaa aatgacaagg  65580 

cagccaggcg cactggctca cacctataat cccaacactt tgggaggcct aggcaagaga  65640 

atcgcttgag gccaggtgtt tgagaccagc ctgggcaaca tagtaaaaaa atttttttaa  65700 

ttagctgagc gtggtggtgc atgcctctat tcccagcttc ttaggaggat gaggtgagaa  65760 

gattacttga gcccaggagt tagaggttgc agtaattatt atcaccactg tacttctgcc  65820 

agggcaacag agcaagactc tgactcttaa aaaaaaaaaa aaatgaaaac acaagctacc  65880 

gctgagaaaa cacatttgca aaacgtaaca gaacaacgct taggtccaga atatatgaaa  65940 

attgtacata actcagtaag aaatagaaaa aaagtagtag taaaaatcac atacttcaca  66000 

aaagaatatg tgtggtcggg cacagtggct cacacctgta atcccagcac tttgggaggc  66060 

cgaggcgggc agatcacctg atgtcaggag ttcgagacca gcccaaccaa catggcgaaa  66120 

ccccatctct actaaaagta caaaaattag gcaggtgtgg tggtggtcac ctatagtccc  66180 

agctactcag gaagctgagg caggagaatt gcttgaaccc aggcagcaga ggttgcagtg  66240 

agccaagatt gcaccgttgc actccagcct gggcgacgag caaaactcca tctcaaaaaa  66300 

aaaaaaaaaa ttatatgtga atggccagtg agcccttgag aagatgcaga acatcgttgg  66360 

ccgttcagga aattcaaaaa gaaccacagt gagataccac ccatacgtac tagattgact  66420 

aaatttaaaa gactgaaaat aacaaatgtt gacaaagatt tggagcaact agaaatttag  66480 

gagtgtaaaa tggtacaagt actttgaaaa atagtttggc ggccagacgc agtggctctc  66540 

gcctgtgatc tcagcacttt ggggtgccta gacaggcaga tcgcttgagg tcaggagttc  66600 

aagactagct tggccaacat ggtgaaaacc tatctctact aaaaatagaa aaaattagac  66660 

gggtgtggtg acatgtgcct gtaatcccag ctacttggga ggctgaggtg ggagaatcgc  66720 

tggaacctgg gaggtggagg ttggagtgaa ctgagatcat gccactgcac tccagcctgg  66780 

gtgacaaagt gagactccat ctcagcaaaa aaagaaagaa agaaagaaaa atagtttggc  66840 

agtttatttt aaagttaaac ccagtcctca acttagaatg gtttgacttc cgatttttca  66900 

actttatgat ggtgcaaaag tagtatgtct tcagtagaaa ttgtatttat agtacaatat  66960 

tctctcaaaa tgttgtgcag cagcagcaaa ccacagctcc tagtcagcca tgtgatcaca  67020 

agggtacagt gtactgtgtt gccagatgat tttgtccaac cgtaggctca tataagtgtt  67080 

ctgagcacat ttaaggtagg ccaagctacc tattgtgttg agtagtttag atgtattaaa  67140 

agcattttcg ccttaacgat attttcaaat tatgatgtgt ttattaggat gtaatcccgt  67200 

tttaagtcaa ggagcatctg tattctctgg ggtttatttg agacgtagtc tccatctgtt  67260 

gcccaggctg gagtgcagtg gcgtgatctc ggctcaatgc aacctcctcc tcctgtgttc  67320 

aagtaattct cctgcctcag cctcccgagt atccaggatt atacgcgcct gccaccacgc  67380 

ccagctaatt tttgtgtttt tagtagagac agggtttcac catgttggcc aggctggtct  67440 

cgaactcctg acctcaggtg atccacccgc cttggcctcc caaagtaaga aacagaaatt  67500 

tgtttgtcaa ttataaataa atctaataaa agatatatga gttttagagt atattataaa  67560 

accttagtgg aatttaaatg accttaatac attcagagat atactatgtt tatgaattga  67620 

aatactatcc cactgatatt ttgaacatta gtctattttg gtaaatttct tttccctagt  67680 

tatagttatc tagatacatt ttcccctaaa ctcccctcct ttctgtttta tttatctgaa  67740 

ttctagtggc tgctcattaa ttttaattat atgagtatag tacaatttat caatccagtt  67800 

tataatacaa aatatccaaa tatgttgaca catatttagg ttgtttccat tctttttact  67860 

cttacaaata atgctacaat aaggatatga gcattcttat tcatgtctcc ttttggagac  67920 

agggaatttc tctagagtat atattccact ataacagaag tgctgggttg aaaattatat  67980 

acagcttcca atttattata tattccactt cctttcctaa gtgactttat cagtttatat  68040 

tcctacagtc tgagagcttt cattcttcca ttggcttatt ttcagcttgt tacccttaaa  68100 

gttttttcta atcttgattg gtataaaatg ataggttgat attgttttag tatatatttc  68160 

tctttgtctt ctatgaaacg tttgctcatg tcctttgcca ctttttattg ttttattttg  68220 

atttgtagga actctataca tattctagat actaagcatt tgttaaacat attgtgtata  68280 

tcctctatca atctttagct ttatttcttt atttatggtg tcttttttct tatagttttc  68340 

atggtttata gtttttgtat tgtgctgaag aaattcttcc ttacctttaa gaccataaag  68400 

atattctaca tttttcaata aatgttagtt ttccttttca tatttagttc tctgaatagg  68460 

aatttgttta tgtatatagt atgaggtagg ctttcaagcc tgttctgtgt gtctagcccc  68520 

acagtctctt tatttgaata ggattataac aaatcttgat gaatgctaga gcagacctta  68580 

ttcttaagaa ttgttggctg ggcacggtgg ctcatgcctg taatcccagc actttgggag  68640 

gccaaagcag gtggatcacc tgaggtcagg agtttgagac cagcctggcc aacatggtga  68700 

actccgtctc tactaaaaat acaaaaaaat tagctgagcg tgtaatccca gctactcggg  68760 

aggctgaggc aggagaatag tttgaaccca ggagacagag gttgcagtta gccgagatta  68820 

cgccactgca ctccagcagc ctggccaaca gagcaagact ccatctaaaa aaaaataaag  68880 

acttgttgtg gctattcttg tttcattgtg ctttcatgtt aattatagta tcttaagttc  68940 

cagggggaga gaggattaca tcctgttgat attttgactg aaattgcgat tgaagattaa  69000 

tctggggata atttacatga atagggtgta ttataactct gtttatttga tcttctatag  69060 

tatctttcaa taaaagagat acttattact tccataggtc ttatacacct tttgtttaga  69120 

tttcatctca aatgccttat gttttttgtt gtgatcataa gtggtatatg tttaaattac  69180 

attttaagta ggttgctagt gtataagaat ataatttatt tttatatgta gaccttaaat  69240 

ctagtaacat tgctgaatta ttaattctgt aatttgtcca tagattttta ttgggttttc  69300 

tatgcacaca attaatgttg tgaagagtaa taattttgtt tctctctttc caacctttta  69360 

actttttatt ctcctaattt gctttgctat gctagctaga acttcctata aaattaagtt  69420 

gaatttacca tggagttttt tttttctttt ttatgtatct gccaggttgt aataccatag  69480 

agttttggta aataactttt accagattag ggaagttccc ttctcgtcct ggtacaataa  69540 

gagtatttgc ttcagtgctg aattttatca aatgcttgct ttttggggac tgccatctat  69600 

ggaaatgatt atatgcttat ttcctgtaac atgttaatgt agtatatttt attgatagat  69660 

ttttaaaatg ttaaatgtaa acatttttca gtaatagcta atttgtgaaa gggaaggaag  69720 

gaataaacta catatatatg taggtttatt aaatattaag aattcatcca agggacagaa  69780 

aagcaaacat ttgatcattg aaacatattc ctaattcaaa actatatttg ctgatttcaa  69840 

cccattcttt ctgagttttt tattactaaa tttaattttt acctcaaatg cccaccttcc  69900 

tgtagagaag atggtcaata gtaaaatgat tcagagtgta gtggaataaa cagggaaaaa  69960 

tagtagaaga ggattaaaca agagaaataa ctctagcatg tttgtttagt agttacaagt  70020 

aattacaact ttgtggtatc tgaaatatta gttgtgaagg ctggtgttat agcaatccag  70080 

tgaataaatt ttacctgtag gattaaaaga aaggcaaaat aagcatatta ttcactttct  70140 

atttatcttt catttacttt ttaaaaatta acccagatca atatgtgctt aagaacttaa  70200 

acattataaa catataactt aaatttgata tgtatcctgt cagccttcct ttttgtgcac  70260 

aataatattc caacattttt cagtagaaga atataatata tatatatatt taaaactatt  70320 

atggatttga gtaagatacc cagaatactg ttacaatctt aacagtctct cttttttttt  70380 

taattagtta gaaactggaa atatttctaa agtttatttg gatggaagtt tagaagtgaa  70440 

tattgatttc tcttatcttt tccacagaaa tactcatggg ccaggcgtgg tggctcacgc  70500 

ctgtaatccc agcactttgg gaggccgagg cgggtggatc agttgaggcc aggagtttga  70560 

gaccagcctg gccaacacgg tgaaaccccg tctccactaa aaataaaaaa attagccggg  70620 

tgtggtggca cgtgcctgta attccagctc ttggaaggct gaggcacgag aattgtctga  70680 

acctgggagg cagaggttgc agtgagccga gatcacacca ccacactcca gcctgggtga  70740 

cagagggaga ctctgtctca aaaataaatg aataaataaa taaaaataaa aaataagtac  70800 

tcatggatgt ataccaaaaa aataaataca tacacatacg tacacaaaca cacacacgtg  70860 

cacaggaaca ttcattggaa tattgtttgt aatagtaaaa aacaacccat aactctccct  70920 

cagaggacat gaagtacatt catacagtgg gatatcttgc agctatgaga aggaatgata  70980 

tagtttcata ttagtacata caaggcacag tatagtgttt ctaatgtttt accatttgag  71040 

ttctttttta ttaagagggg aagggagtac ctatttactt aattatcatg cacccacact  71100 

gtaacatagt gtgcagcaat taaagggtgt actgacatga aaagatctct aagatgtatt  71160 

gttaattttt aaaatcatga taaaatgagt catagaacag ttatctgatt tcatctaaaa  71220 

agttattcct acatttttat ctttgtaaat tagtattttt gtttttttaa tcacctttct  71280 

gacaaatcta agtgcatatt aaaaggagag gatgtataca tacctaagta ctaacaatgg  71340 

ttacttatta gagctatttg gagcgaggag gttcagactg gagagggtct ttactttgta  71400 

tatctctgta ttgtttgagt ttttatgatg aaactttatt catgtattat ttgtgtaata  71460 

aagaagtaaa aaacaatatg cactcagtac caaaaaatga agttataaag ataaaaatgt  71520 

tttctcgtag taaaaaatat gttaaaaaaa attttttttt gagacgaaat gtcttgctct  71580 

gtcacccagg ctggagtgta gtggcgcaat ctcagctcac tgcaaccttc gcctcatggg  71640 

ttcaggcgat tctctggcct tagccttctg agtagctggg attacaggca tgcgccacca  71700 

cacacagcta atttttgtat tttttagtag agatggggtt tcaccatgtt ggccaggctg  71760 

atcttgaact aatttcaagt gatcaatgca ccttgggctc ccaaactgct gggattacac  71820 

ttgtgagcca ctgtacccag ccaagataat tttttttttt tttttttttt ttgagacaga  71880 

atctcactct gtcacccagg gtggagtgca gtggcgtgat ctcggctcac tgcaacctcg  71940 

gcctcccagg ttcaagcgat tctcatgcct cagcctcctg agtagctggg attacaggca  72000 

catgccacca cgcctggcta atttttttgt attttcagta gagatggggt ttcaccatgt  72060 

tgcccaggct ggttttgaac tcctgagctc aggcagtcca cccgcctcgg cctcccaaag  72120 

tgctgggatt acaggtgtga gccaccgtgc ccggccaaaa atattttgaa gaaaataaaa  72180 

tacccacagt agcctcacca cccacattta tccagagata actactgtta aagctttgaa  72240 

aatatcctcc cagaggtaag gaacatttta tggaggacat ttaatgctaa accaaggaaa  72300 

gcaagagaaa gatccccaca taaaaagttt acgctcctga cctcgtgatc ctcccgcctc  72360 

ggcctcccaa agtgctggga ttacaggcat gagccatcca gcctggccaa cgtggtaaaa  72420 

ccttgtctct actaaaaata caaaaattag ccgggtgtgg tggtgggcac ctgtagtccc  72480 

agctactcag gaggctgagg caggagaatt gcttgaacct gggaggggga ggttgcagtg  72540 

agccgagatc gcgccattgc actccagcct ggacgacaga gtgagactcc gtctaaaaaa  72600 

taaataaata gataaataga taaataaata aataaagttt acacttagct gaacagacag  72660 

tgggcatttt tttttttttg gagtagaaaa atgacatgat aacatgcaac ttactgtctt  72720 

atggttttac tttttgttgt atccccagtg cctatataac acataatagc cattaataag  72780 

tatgtgtctg agaaatgagt gatggtgatc tgctaaccat tggtgaaact cttctagttc  72840 

caaaacccat ggttaagaaa tcatagtggt tgactgttaa aaaaccaccc actgctcaat  72900 

aatattggac agataaccct aaatattact atctgtagac tgagcacagt ggctcatgcc  72960 

tgtaatccca gcactttggg aggctgaggc aggcggatca cctgaggtca ggagttcaag  73020 

accagcctga ccaacacgga gaaaccccgt ctctactaga agtgctatat tggtcggacg  73080 

tggtggtgca tgcctgtagt cccagctact tgagaggctg aggcaggaga atcgcttgaa  73140 

cccgggaggc ggagattaca gtgagccaag attgtgccat tgcactctag actgggaaac  73200 

aagagtgaaa gtctgtctca aaaaaaaaaa aaaaatatat atatatatat atatatatat  73260 

atatgtatat ttgtagctta gatttagcac caatgactaa taccactgtt ttttcaaatc  73320 

attacaagac agggaaaact ctctttagaa tagatagtct agggtggcat agaaagcctt  73380 

gtttaagaaa taatactggc caggcatggt ggctaacacc tataatccta ccactttggg  73440 

aggctgaggc gggaggattg cttgagctca ggagttggaa accagcctga gcaatatagt  73500 

gagaccttgt ttctattaaa aaaagaaaaa aagaaataat acctaaccat ctcatctgcc  73560 

acggggctcc agccttcttt gtctctttca agccttgtct cacccagaac acttctctat  73620 

agagaatgga atgaatcagt tacttacgat gaaagagata gattataaaa actgtagtat  73680 

ttggccattt tgtatttgtg cctcagaggt caaattaaaa ctgcttaatt ttggaaattt  73740 

gtatgtacat aaatgtgcat aaaggatcat tttaacccta tagatagtta tcctggagcc  73800 

taagatgaag tttctgaatt ttttagggaa acattaattt gtattgtttg tgtttttctt  73860 

cttagtttct gccactgcct tctacaaagc acaacctgta attcagttca tgtgtgaagt  73920 

tcttgatatt cataatattg atgagcaacc aagacctctg actgattctc atcgggtaaa  73980 

attcaccaaa gagataaaag gtgaattaat tagcatttag cacaacttaa ctataaaatg  74040 

catggatata acaacctttt attaaaatgt tttcttatat aattaaaatc tatgtaacat  74100 

aaccagtaaa actatacatc aattataaaa taaaatatta cattaaattc attactataa  74160 

catcttaggt ggtatttgaa agaaatgcca agtaatggag ttagtatcac taccagctaa  74220 

ttttttgtta atactttccc ttactagctg aagggataag aatgtctcat gggaaaatgc  74280 

tttagtaata ctgttaaaag taggaagctc actccaaaaa tatttgttat attttataac  74340 

tagaattata gaactagaac atattctaat ataatgactt ccttattttt ctgaaatgat  74400 

agttatttat tttagtcctt taaaaacgta taaatgtggg gctagcctgt ttcatgtgtt  74460 

gttctagaat tatagttatt taatataagt tatagagttg actgttgatc ttatctatta  74520 

tacttagtaa ctaaaatttg tacagtgctg ttgcatcata tgtacattta actcagataa  74580 

attcatctct atgtggctgc ccaaaaataa aaataaaaat aattttaata gtgttctgaa  74640 

atctgtattt tatatgtatt tagtctgata ctccctaatc agaatgaata ggataagttc  74700 

tatttatatt gttagatctt aaatagccag aaataattat gttgttttta agattttacc  74760 

tatttattgc agataatttt cagcttgtgg tttgaatgaa gcatttaagt ttgttcactg  74820 

aacatctttc agttccccca aatcaattag agtagtttaa tacattctgc ttgctccagt  74880 

aataattcat tcttcgccat tcagtaacca agagagagat agtcattgta ataaaatatt  74940 

aaaaggaaga tccaccctgc tttgaaaata agcatccatt tatctcaagt tatttaaatg  75000 

ccaaagtaag aaactgttta tgtaactgtt ttgcaaccat accattgtcc tttcatgatc  75060 

tgtattaact gcacagctag cattgtcagg aggttagtgc attacctacc attaatatgt  75120 

gatcatctaa atgccatggt ttccagtgga gttgctgctt agttaccacc tctgatatca  75180 

tgaagtcact tacattattt tgcggtaact atgcaatcaa ctcatatcac cactctatca  75240 

cagaaaatac aagatgtaca gaacaaggat tcaactgctg cccgaagagc atggactcga  75300 

tcttaacttc aactgctcag gggcccaaag aaatgactga aaaaatgact agaaagcata  75360 

ataaagttga tgttatagtg aaggtaaagc caagtttata ggttaaatat ttattaaagc  75420 

caaaagtgtt tttttggttg gatggagggt ttggggaggg acctgggcag agaattatct  75480 

agtccacttt ttaaaaattt caactttttg ctagcaccta gattttggtc taattcttag  75540 

gtatttatga tcctagtttg ggggtggaaa aatctgggtg ggatccaatt gacaaactga  75600 

ttattttttt cttcattcca agtaaaatag ggcttttttt ttttttaaag aaggctcttt  75660 

aaagtacatc atgtattcct actacagtaa cccaagagaa taagagtttt gtgttctctc  75720 

ctgtatctat gggtttttta gctggtatga agaatttgat gctagctgtt aaataatgac  75780 

acaaagtgtg caataaagaa tagattttct tagtatattc atctttttcc agttgaactt  75840 

gtacctaaat atttaataat aactttggag tggtttcttt atccagtaac tcgtgatagt  75900 

taaacagcag aaatactggg aaaatgtata agtaccatat atatatatct atatatgtgc  75960 

caacttattt ttagtaaaag ctttataggc ttggagaacc ttattaatat ttttttaatt  76020 

caaggggaag agttgaaaat aaattgctaa gtggtgcaaa taacagaaat ttgttttaga  76080 

cttttctatt gtgttctccc ctgaacataa tatttttacg tcttgtttct tcatattatt  76140 

agtatttcct tcttttaaga tcctccttcg atagtatttt attttctagt ctcctttata  76200 

atataaagac atagtaattc tctagttgat ctgacatttt tgtcttataa aggtagttgt  76260 

aatgaaaaat tactactcac tgattcaagg aggagcactt ccaaagaaaa acaaacccat  76320 

accaatctgg tacagggatg gataccgtgt ccatttaaca tcttaatttg ttctgatcta  76380 

tcagaagaaa atatcattta tatgattgag ctttgtgttt ggtactaatt ttcttaccta  76440 

attgcaggta gcagttaggt aagaaaataa attttaccat agcaggcatt ctcaacctta  76500 

gcagcattga cattttgggc tggataattc tttgttggga taggggtagg gctgttctct  76560 

gcattacagg atatttcata ctatccctgg cctctactca atagaaagca gtagcatctc  76620 

tagtcatgcc tatcagtttg tctccagaca ttgccaaatg tcccctgggg gacagattgc  76680 

cctctggcta agaaccactg cagtatagga atcacaaata tgaaagagaa atatgacaaa  76740 

gagtaataac cataagtatt atcagggaac taaaagttgt tctccatcta ccccattttg  76800 

gactttatcc cttggagtct aggccaaact ttagaaagga gttgcttatc tgtgacctct  76860 

gtgtacctgt taactcttct ctaggctaag actgcactaa ccacatgtag ctacttaaat  76920 

ttaaattaat taaaataaag gccgggcgtg gtggctcacg cctgtaatct caacactttg  76980 

ggaggccaag gtgggtggtt cacctgaggt ctggagttca agaccagcct ggccaacatg  77040 

gcgaaacccc atctctacta aaaatataaa aattaactgg gcatagtggc gggtactgta  77100 

atcccagcta cttgggaggc tgaggcagga gaatcacatt aaccctggag acagaggttg  77160 

cagtgagcca agattgcatc attgcactct gacctgggca acaagagcaa aaaactaaaa  77220 

aaaaaaaacc taaataaaat taaattttca gtttcttagg tacaccagct acatttctta  77280 

tgcttagtaa catgttatta gtgattacca tattagcata aatgtagaac attccatcac  77340 

ctcaagaaaa ttctctttga cagcactgct tcagaaaatt catctcgaag aacttcagcc  77400 

aacagcttaa agcccatttc ttcacattct agagcaggcc tgggatcctt gaacccctag  77460 

agtccacaga tggacggcag ggatccaaga actcctaaaa tcatgtgcta aattatgtat  77520 

atgtgcattt tgctgagagt ttattgctta catcagattc tcaaagggat cttgactcca  77580 

taagagggta gggatcacct actttaggaa ttattttggt tacatttgat ttttaatagt  77640 

attggaaaag agctgtgtca ctatattata cctctataaa agtgtcactt tgcttctgtt  77700 

aaaaatgcct ggaatttttt tctcctgctt tataaatctt taaaggactt ctttcttgag  77760 

ctttacaaaa ttctgatctt caagcagtat gtgatgactg ggctaggtaa atatcacata  77820 

atttgaaatt atggaatacc ttgagaatta ttggatctcc tctttcattc ctccttccct  77880 

ctcccagcat aaatacctga atttattata aacaggattt tttattaatg gaagattttg  77940 

gcccttgatc tatgggcttt gcaaatttta tgattttatt ttttaatgtg tagagcttga  78000 

tggggtaagg aaaaattttg ccattaggtc tgtcatgact gtgaccatta ttagcaatgt  78060 

tatatgtaaa atctggtgtt tatatcatct tgcctgtatc acagaatttt ttgtctgttc  78120 

agaattgagt ttttatggta atgaacaggc tttataagta taaatatttt acatgtgaca  78180 

gttctgtaac ctccattttt cttgttggga acaggtttga aggttgaagt gactcattgt  78240 

ggaacaatga gacggaaata ccgtgtttgt aatgtaacaa ggaggcctgc cagtcatcaa  78300 

acgtaagaaa agtttgtcag agcagcgatg gtgtgaggca gcttgctcta gttagtgggg  78360 

ttgggagttt ttctggctca taatgggcaa gaattgttca tgtgtacttt tttttcctca  78420 

gctttccttt acagttagaa aacggccaaa ctgtggagag aacagtagcg cagtatttca  78480 

gagaaaagta tactcttcag ctgaagtacc cgcaccttcc ctgtctgcaa gtcgggcagg  78540 

aacagaaaca cacctacctg ccactagaag taatgccttc acactgctaa ttaataccct  78600 

gttgttcatg attcttttgg ggtcttttat ggccgataac ttacctcata cagaacattt  78660 

attttggaat atgaactgtt tttaagtttt aatttattct aaattttctg taatgaaata  78720 

acacgaaaca agttcatcca taatcctacc actctaatgt aaccactgtt aacattttgg  78780 

tatactatac ttctttcagt cttcatctgg tgtacatttt acttaattat acttaattac  78840 

tgtagagctg tcttgtttac tactttttta cttaacatat tgaaaataag tggtttaatg  78900 

aagttgattt taaattttta tttacatgta attggcacta agtaagagct aaaaaaaaaa  78960 

gatatataca tgtagtacaa aacttttttc catttgtagg tctgtaatat tgtggcaggg  79020 

caacgatgta tcaagaagct aacagacaat cagacttcca ctatgatcaa ggcaacagca  79080 

agatctgcac cagatagaca agaggaaatt agcagattgg ttagtactta accttagaaa  79140 

tgagaattta aaacatatta gggtgaactg taatactaga gaaccatgtc cttatcaacc  79200 

cataccttat gaccatttca tggactgtca gaattaaaag caatcatgga agtaatctaa  79260 

tgttcttgat acaagccttg gtgggctata tgagaagggt taggtccttc tcatttaacc  79320 

ctgagctttt taagtagatc cagggaacag atcctctcag aagaaatgtt tccatttagt  79380 

aaactggaac ctccacctaa aagaggtggg aaataggagg aaaagtcaaa gaattatgac  79440 

tagcaatact aaaattcttt tttttttttt tttttttttt tgagacggag tcttgctttg  79500 

tcacccaggc tggagtgcag tggcacgatc ttggctcact gcaagctctg cctcccaggt  79560 

tcacaccatt ctcctgcttc agcctcccca gcagctggga ctacaggcgc atgccaccac  79620 

gcctggctaa tttttttgta tttttagtag agacaggatt ttaccatgtt agccaggatg  79680 

gtctccatct cctgactttg tgatccgccc gcctcggcct cccaaagtgc taggattaca  79740 

ggcgtgagcc accgcacccg gccaatacta aaattcttaa cactcagtct aagattgctt  79800 

agtccccagt atcacagtgg cagctgtaca gtctgaataa agaaatggct gggctcagtg  79860 

gctcacatct gtattcccag cagtttggga ggccaaggcg ggtggatcac ttgaggccag  79920 

gaatttggga ccagcctggg aaacatggca aaatgccatc tctactaaaa acgcaaaaat  79980 

cagtggggca tggtggcatg tgtctgtaat cccagctagt caggtggctg aggcatgaga  80040 

ataacttgaa cctgggaggc agaggctgca gtgagccgat cacaccactg cactccagcc  80100 

tggacaacag agtgagactc tgtctcaaaa aaaaaaaaaa agaaaaagaa ggtcgggtgc  80160 

ggtggctcat gcctgtaatc ccagcacttt cggaggccga ggggggcgga tcacctgagg  80220 

ttgggagttc aagaccagcc taccaacata gagaaactcc gtgtctacta aaaatacaaa  80280 

attagccagg catagtggcg catgcctata atcccagcta ctcaggaggc tgaggcagga  80340 

gaatcgcttg aacccgggag gcgcaggttg cggtgagtcg ggattgtgcc attgcactcc  80400 

agcctgggca acaagagcga aactctgtca aaaaaaaaaa aaagagagag agagagggag  80460 

ggagggaggg aaagaaagag aaaaagagag agaaagaaaa gaaagaaagg aaatagaaga  80520 

tagctttaac cacgtaaggt ctctgtgctg tctcattgtt ctaaatgagg ggaaggaagg  80580 

cgttaccaat accgctttat aaaactcata gagtaaggca aaactcaaga ttaaagggca  80640 

tctgaatctt atctggctct gttctcgaat accattttaa ctgcccaagc aaagagaaaa  80700 

aaatctggaa atatgaatat ttcccaaaac aacttaataa tacttccaaa agcaatttta  80760 

aagattattg aaaataggga tgcaaaactg gctcttttaa tttatttttt aaccttagta  80820 

atttcacctt tggcaaaaac tggctctttt atttggtaag ccaactgcag aaaaaatact  80880 

tttttttttc cttattgact cttctgtaaa gagtcaaaga aagttattac atgatattta  80940 

attaggaaaa tatatgctgg ttttcatctt ggatttttct ctgattctac tataagattt  81000 

taaaaactct caaaatcaga gactaagacc tcttactttg tctataaaag tctcaataac  81060 

tcactgttct aattcattta ttacagctta actgttcaga aagtatcata tggtagttta  81120 

aaaaaaataa aacagacttt ggagtctaac aaccctgggt tggaagtctg gcttctccac  81180 

ttacttactg ttactgttac tattattata tttatagtat ctggaaagat aatgcagtga  81240 

ttaagagtag acactctaga atcagaatat acatggtttc acattctgtc tacatcactt  81300 

acttagctgt gcggtttttg gcaatcattt tactttactg agctttagtt gtatcctctg  81360 

taaaatacag attataaaag aactgttttt gtagctataa aatacttgtg aaaatgtatc  81420 

attaagcact tagcaccaag tacatcatgc agcaagtcat agtatattag ttgttatagt  81480 

atagtcgtca ttattcgctg taaccttatt acaggataca ctgaagtaca gaaatgcatg  81540 

gcaaataaga ttgaaagaga tgccccattg gtgcctaatt tagaaaatgg ggcttacacc  81600 

tgtaacccca tcactttggg aggccgaggc aggactatca gttgagccca ggagttcaag  81660 

accagcctag gcaacatagt gagaccccat ctctacaaaa aaaatgttaa ttagccaggt  81720 

atgtggcatg cacctatagt cccagctact caggaggctg gggtgggagg atcgcttggg  81780 

ccccaggaga ttgaagttgc agtgagctgt gattgcacca ctggatgaca gagcgagacc  81840 

ctgtctcaaa aaaaaaaaaa agaaaagaaa aggaaaaaga aaagaaaatg acttttcctg  81900 

cttattgtgg agagattcta tatagcagca tgctttaagc atgaatttca gtgagattca  81960 

acactgaatt acatgaagtt ctttgattat atgtatggga atatataaaa attataacct  82020 

gtgactcata ctggctttct tatctgtctt taagtgtatt ccattaaata aattttataa  82080 

tatggcactg aaaatagtca agtaaatttt atataaatta taaatcaaat aatttttaaa  82140 

agctttaaga tttttaatat ttcctatcaa actctacaca aaataaattt taatagaatg  82200 

tatccagatc tcccatagtc agaggttctt aacctctttt taggtgagat atttctttct  82260 

ccatccaaaa gcatattagg ttcaatcata caaaattaac attttcagct gggtagtaca  82320 

tagtggtgca tgcctatgtt cccagctatc taggaggctg agagaggaag atggcttgag  82380 

cccaggagtt caaggccagc ctgaataaca tagcaagact ccatctcttt aaaaaaaaaa  82440 

aagttttatt atcattttca tggatttttt ttttcttttg agacagggtc ttgctctgac  82500 

ccccaggctg gagtacagtg gtgcaatcac agcccactgc agccttgagc tcccaggctc  82560 

aagcgattct ctcacctcag cctcccaaat agctgggacc acaggcacac agcaccacac  82620 

ctggctaatt ctttttaatt ttttgtagag atgaggtctt gctttgttgc tcaggttggt  82680 

cttgagctcc tgagctcaag cagttctccc acctcagcct cccaaagtgc tggaattaca  82740 

gatgtgagcc accacgccca gcctaatttt ttaatttttt tgtagagaca gggtctcact  82800 

atgttgccca ggctagtttc aagcttctgg gcttgagcaa tcctccagct tggcctccca  82860 

aaatgctgag atcacaggca tgaactacca tgccaggcca aaatgtatta ttcaacctaa  82920 

tgcatacata caaattttgt ataaattacc aggaggtcac agaatttctg cagtccattc  82980 

atgacccatg gtccccaggt taagattcgc tgttctgtag ttagagcacc attgattaga  83040 

cctgttggaa aatatattat ggacacagtg aagaaaaaaa agagggttct aatgcattaa  83100 

agtaggggat ttgggggaat tttgagagta actacaaact ttttctattt ttaggtaaga  83160 

agtgcaaatt atgaaacaga tccatttgtt caggagtttc aatttaaagt tcgggatgaa  83220 

atggctcatg taactggacg cgtacttcca gcacctatgc tccagtatgg aggacgggta  83280 

aagtctcttg ttaatgtttt aatcatacac atattgtctg taagtatgaa gagaaaggca  83340 

tatcagaaat atttcaattc agcgatttga aatgtttact ttctgtttat tgaaaatttt  83400 

tgttcttttt caccatgtta tttttttctc ctcgtgtaga atcggacagt agcaacaccg  83460 

agccatggag tatgggacat gcgagggaaa caattccaca caggagttga aatcaaaatg  83520 

tgggctatcg cttgttttgc cacacagagg cagtgcagag aagaaatatt gaagtaagac  83580 

atgtcattac cttggctttg ggactttttt gtgtttagac tttaaattac tcatctaatg  83640 

ttctaacaga tgttgcctta atatgaagta tatgtaatca ctgaaccatt tttttttttt  83700 

tgagacagag tctcactctg tcacccaggc tgaagtgtag tggcgtgatc ccagctcact  83760 

gcaacctcca cctcccaggc tcaagcaatt ctcctgcctc agcctcccaa gtagctggga  83820 

ttacaggtgt gtgccaccac gcccagctaa ttttgtattt ttagtagaga tggggtttca  83880 

ccatgttggc caggctggtc tcaaactcct gacctcaggt gatctgcccg ccttggcccc  83940 

ccaaggtgct gggattacag gcatgagcca ctgtgcccgg cctagtcact gaacctttaa  84000 

aaatgtttct tcttgaccag gcacagtggc tcacacctgt aatcccagca ctttgggagg  84060 

ccagggcggg tggatcacaa ggtcaggaga tcgagaccat cctggctaac atggtgaaac  84120 

cccgtctgta ctaaaaatac aaaaaattag ccaggcgtgg tggtgggcgc ctgtagtctc  84180 

agttactcgg gaggctgaag caagagaatg gcatgaaccc aggaggcgga gcttgtagtg  84240 

agccgagatt gtgccactgc actccagcct gggcaacaga gtgagactct gtctccaaaa  84300 

aaaaaaaaaa aaaaacttct caatagttcg gtgaaaaaat ttgttagtca tagtaaattc  84360 

cttgattcat tctattagac atccttatag actactgtga atggaaaaaa cacaagctca  84420 

aaccatgttt tttctctgct ctcacaccag agcaatcaac acagaacact cttgtgacta  84480 

aatgtgggga gggtttcccc acacaccaag caaacaatca gttctgcagt ggacaccagc  84540 

tgggtgtcct ccaattcagt tattacacta tcttcctgga aatagcatca gattccacag  84600 

attcagggtt cactcccaca aggctgcact ctgcttcaga tgccagtagc aagtccaggc  84660 

ctctggtcat gggttcccat gaccccctct tcaagataga ttcgtctgat agagcagctc  84720 

acagaactag ggaaacactt actatgttta ctgttttatt ataaaagata ttccaaagga  84780 

tgcagtaaag atatccatag ggtgaggtat ggggacggag tgtggagttt acatgccatc  84840 

cctgggtaca ccaccctcca ggaacctttg tgtgttcagc tggccagaag ctctccaaac  84900 

cccatccttt tggattttta tggatgcttc attacatagg cctcattgat taaactgtta  84960 

gccattagtt atcaacttaa ccttcggccc ctttcgcctc cttggaggtt ggggatgtgg  85020 

ggctgaaagt cccagccctc taatcctgcc ttgcctttct ggtgaccaga ccccatcctg  85080 

aagctaccta taggctacca gccgttaggc aatcagtatc atataaaaaa gataacactt  85140 

aggagtttct aaggatttta ggagttgtct gctaggaaat gggaatggcc aacaaatgca  85200 

tatttcacaa tatcacaact actttttgtg ggatagtagc agcaagcatc attgtctttc  85260 

gatgacagtt taggtataat tcccagattt gccactacct ggatttatta ccatggataa  85320 

tttatttaat ctcattattc ttcaatgttc acctttgtaa aatagagcta atcatatctt  85380 

ctgttaaaat aaaaacttca gacaaattaa atttaacaga gtttataatt gagcaaagaa  85440 

tgatttgcaa atcaggcagc tcctggaaca agaacaggtt cagagagact tccagcagcc  85500 

gcatggttga agaagattta tggacagaaa aaggaaagtg gcatacagaa tatggaaatg  85560 

aagtacagaa acagatggat tggttacagc ttggcatttg ccttatttga agatgatttg  85620 

aacagttagc tgtaattgat tggctaaaac tcagtgtttg gtacacaagt agcttatcca  85680 

ctatttaccc atccagttag gttacagttt tttgtttttg ttttgagaca gagtcttgct  85740 

ctgtcaccca ggctggagtg cagtggcgtg atctcggctc actgcaacct ccgcctctca  85800 

ggttcaagcg gttctcctgc ctcagcctct agagtatctg ggactacagg cctgcactac  85860 

tatgcccggc taatttttgt atttttagta gagatggggt ttcactctgt tggccaggct  85920 

ggtctcaaac tcctgacctg aggtgatctg cctgcctcag cttcccaaag tgctgggatt  85980 

acaggcgtga gccactgcgc ctggcctagg ttacagttta cgatgttcag agaaacctct  86040 

agactgaact taaaagatgt aaggaggtag ctttaggcaa aacttaattt aacagttatc  86100 

ccctttgatc tatcccccca attttttttt ttaatggatt ggcattgatg tcagtcacca  86160 

tcataaactt acttatttgg tctcaaatcc cactgggaaa tagcagaaca atgggttttg  86220 

taaaatggga acaaggactt caggttactt tttcctaagg gtaagagtag aggggacctc  86280 

cttgtgctga aatttcctgt tttcaggaga aaaacaaaac ctggtctatt ttaggatcta  86340 

tctctttctt taatgtttca gtgtaattgt ctcacgctta gcatgagtga ctccattttg  86400 

gtttggtatg gtctgttggg gcctcatgca tgagcttagt ccaaaacaat ggcctcccac  86460 

aattttgttt aaaaattcct cccttttggt taggtcctca cttaggtaag agtgtgacca  86520 

aaacttagga ccttagcacc actctgttac caagattttg ggtttctggt ctcagtacgt  86580 

catttataag tatggtgttc ctcatgctca tacatttctt tgagtttctg ttccaattca  86640 

agagagacca tttgacatcc tacagatggc catatgcaaa cacttaaaac ttttgagaga  86700 

atatagtatc ccagggagac tactattatg actctcagga gaataaccct aagagtttgg  86760 

agtatgctcc ttagccaagg tccccatgaa ccaagccacc taaaatcaaa tagatcgaag  86820 

aataagctag aataagagtc tacttgtttc aaccaagcac cctgtttgtt aatcccctac  86880 

gactgaatct gttaatatcc aatgtattcc tccatgttca ataagaagta gcagcagctg  86940 

cacagatact tctgtttagc cagtaagtaa tctagagcaa ttctattatc tagcacaact  87000 

ttagcaagat aatttaaagt ctcttgtata accatagtct ttgcagtaga atctgctaaa  87060 

gagcctataa atttctaata ggctagaaaa tttagagaga taaatttcta atcattgcct  87120 

cattacatta actccaaacc ataggccagg cgcagtggct cacacctgta atctgcaatc  87180 

actttgggag gctgaggtgg gcagattgct tgagctcagg agttcaagac cagcctaggc  87240 

aacatggcaa aaccctgtct ctactgaaaa ttcaaaaata atccgagcac agtggtgcac  87300 

gcctgtggtc ccagctactc aggaggctga agtgggagga ttgcttgagc ccaggaggca  87360 

gaggttgcag tgagccgaga tcacgccact gcatcccagc ctgggcagca gagccagacc  87420 

ctgtctccaa aaaggaaaaa acacaccata gaaaaataaa ctaacaaata atgcccatcc  87480 

agaagagtga aggcctcctg gcactattct ctttaacctg tattgacaat gttctctttt  87540 

tttttttgag gctggagtgc agtggcatga tctcggctca ctgcagcctc tgcctcccgg  87600 

gatcaaacaa ttgtcctgcc tcagcctccc aagtagaaca ggcacgtacc accacgccca  87660 

actaattttt tgtattctta gtagagcggg gtttcaccac gttagccagg atggtctcca  87720 

tctcttgacc tcgtgatctg cccacctcgg cctcccaaac tgctgagatt acagttgtga  87780 

gccaccatgc ctggccgaca attttctctt taaattatga tgtaggttaa gaggagttga  87840 

ccagtgctct gtttctgact gattatgaag caaaaaaggt accattaaaa tttctcaccc  87900 

acattggccc ttcatcttcc ctctatcaag gcgtaaactt ctctgtgtgt gagggttttt  87960 

gttttttttt gttttttggt ttttgttttg agacggagtc ttgctctgtc accaggctgt  88020 

gatcttggct cactgcaacc tccatctccc gggttcaagc aattcccctg cctcagcctc  88080 

ttgagtagct gggactacag gcatgtgcca ccatgcctgg ctaatttttt gtattttagt  88140 

agagatgggg tttcaccatg ttggccagga tggtctcgat ctcctgacct cgtgattcac  88200 

ccgccttggc ctcccaaagt gctgggatta caggcatgag ccaccacacc tggccaatat  88260 

gaggtttttt ttatccttca caaataaaag tataccttgt gagtgtacac aagagacccc  88320 

tttttcagtt tagttgttca taacaggcat gaacttggaa aaaattgaga gccaaaagcc  88380 

tcatgatagc agagaagtct tgatccacaa tcttgggaaa tctgtccaca tctaggaggc  88440 

catctgcttc tcgggagaaa cttacctcat tagctttacc ttaagttctc cctctgatgg  88500 

gtgtgtggtt ccaagagtct gggtgggcct ttctaagttg tgagattaca aacccaagct  88560 

tcagggtcct gaagtttcgc tgcagtgtgg gtgacaaggg gagtctttct ctgatgtgtt  88620 

tccaaaagat ccagcctctg aattctatat catgaagggt ttgcttgtcc tgagtcagtg  88680 

gtccatgaaa agctttcttt acctggtgaa aatacacttt ggcataatac attacagcct  88740 

tgcagcattt agtcacgtta aggtttagga gcataagata cagaaggttc tgttattagg  88800 

agcataagcc ttccagtgac tatttcataa gggttcaact tttgttttcc catggaagtg  88860 

gatctgtttg tcatcaatct gaaacatctt tgaccaaggc aatccagatt attcagttag  88920 

ttttgcctaa tgctcttata tctgtaatac cttatttaac tgttttacag ccagtccagt  88980 

gaggcaagta tctctatcac tggagatttc ttcagcaatg ttctatgaga gaaacacatt  89040 

tcctaataac cttttagctg ctgttatagc atcagcccac ttgtatgaga aagctcctgt  89100 

acaaccagaa aatatgcact gaaaatcaca attgaatgaa atccctctgt aaagtgttca  89160 

gatgtagcag aaaggtacct gaagttttgg ttgtcttctc aagattatgg gtttgacaaa  89220 

ctatacattg gtcataaacc attttagcaa tttagaacag tcacaacacc aatatatatg  89280 

taaggtgttt gtttgtttgt ttgtttgttt tgagacatag tctcactctg tcacccaggc  89340 

tagagtgcag tggtgcgatc tcggctcact gcaacttcca cctcccgggt tcaagcaatt  89400 

cttgtgcctc agcctcccaa gtagctggga ttgcaagtac ctgccaccac acccagctaa  89460 

ttttttgtat tttttaagta gagacaggct ttcaccgtgt tggcccaggt ggtctaaaac  89520 

tcctgacctc aggtgatcag cccaccttgg cctcccaaag tgctgggatt acaggtgtga  89580 

gccaccatgc ccggccagta tatacatttt atctcttcct tgatgaatca tggaatacag  89640 

cttctagtaa tggaattttt aaggactcag gaaggagcag gcagccggct gtccagtctc  89700 

tctccatgag tccatgctta acactggaat tgtatcctct tacatagcaa ttttctttct  89760 

ccaatggagg tgcacagcac tgtttattag atgggttatc ataggtagtt tgacctggac  89820 

catggagttc attcaaatta tgtatcttaa tagtttcagt actgactgag ttagcatgaa  89880 

aatctggcca agtattttct tggtattcat ttaattcttg tgctgcttga gttagcagtt  89940 

ttatatatca ctctgtctct tcaatatggt tctggtaatt cttactcagt ccaaacgata  90000 

tgatcctaaa gttaccagaa acctatcttc aggagtgctt accaaggtcc atttcatctt  90060 

ttccattaac ctccttgaag acaaaatagg attttatttg cttgtgaagt tatttttaat  90120 

aactgccata catttattta tttatttatt tatttattga gacggaatct cgctctgtca  90180 

tccaagctgg agtgcagtgg tgctatctcg gctcactgca acctcctcct tcctggttga  90240 

aactattctc ctgcctcaga ttcccgagta gctgggacta caggcgcatg ccaccatgcc  90300 

ttgctaattt ttttgtattt ttagtagaga tgggtttcac cttgttggcc agactagtct  90360 

cgaactcctg acctcaagtg gtctaccaac cttggcctcc caaagtgctg ggattacagg  90420 

ggtgagccac ttgcacccag cctgccatta ctttatttat ttatttattt atttagagac  90480 

ggagtctcgt tctgtcaccc aggctggaat gcagtggcac aatctcggct cattacaacc  90540 

tctgcctccc agggtcaagc agttctcctg cctcagcctc tcgagtagct ggtattacag  90600 

gtgtgtgcca ccatgcctgg ctaatttttt gtatttttag ttgagatggg gtttcatcat  90660 

gttggccagg ctggtctcga actcctgacc ttgtgatctg cccacctcag cctcccaaaa  90720 

tgctaggatt acaggcgtga accactgcgc ccagccgcca ttactttgaa cagcagaaac  90780 

cgcaattact tttgcaccaa cctaatatta gaaactgctt tagaattaag taattaactg  90840 

tggaaatgac tttaaatggt cataaagaca caattgagaa ggaaatttgg ttatttctgt  90900 

ggcctacaat agtttaacgt aataaccata attatgtctg ataacatata ctgagataca  90960 

tgagaatttt cataatctta tacaattttg gaatatatat taatatttat aaaaatataa  91020 

ctcgatggag tttaaacatc acttcttatt tgacactgtt tctcatgtaa ttttacgtat  91080 

aaaataagcc tgtttattat ctcttttgac tgttgtaggg gacctctgta acatcccaaa  91140 

gttaatttga ggtcaaaaaa agacttaatt ttgaatttga aatttgattt ggggaagctt  91200 

gtccaatatg tcaaagattg aaaacacttg gcccaaatag gatcacaggt cactgtgaaa  91260 

taagtcattc atttagccaa ggtgatcatt aaaaggtttt ttaaaagcaa aacctttatt  91320 

atttgataga gaggagactc aattttctag tcaacagacc tgaaaaagac aatatgatac  91380 

agaatctatc tctccttctt tcctctctct ttttttttgt gcagtttact caaaaggtga  91440 

acaaaaatat tttgctgtta ctgaagcttt ttatttgcct tttatagaaa atcttttaaa  91500 

agagggaata aaaatattga aatcttatta gaagcttctg cacattaata ggcatccgca  91560 

tccttggatg aaactaagtt gggggccttt tttttttttt ttttttttga catagggcct  91620 

cactcttttg cccaggctgg agtgcagtgg cgtgaccatg gctcactgcg cctcagcctc  91680 

tcaggcttaa gtgatcctcc tatgtcagcc tcccaagtgg ctgggaccac agggacttgc  91740 

cactatgctc tgctaacttt ttttcttttt ttgtagagac aaaatctcac tatgttgccc  91800 

aggctagttt caaactcctg gactcaagtg atcctcctgc ttcggccacc caaagtacta  91860 

ggattatagg catgaaccta gagccctcat ttgtaaatag acttcttaaa gtgcagtatt  91920 

attcattttg aatgttctac tataatttta aattacataa agtgagattt caccatttca  91980 

gtaagtgttt gctgctttag ggtcctaaca tttatgagtg tatagctagg catagctgta  92040 

aggtagaata ctcagttctt cagaaattaa ggatcccatt ttcccttgaa tcttggcttt  92100 

ggctgtcaga tcccattgat catccaatga tttttccatg cctaaacaca caagaaaaag  92160 

aaacaaaggg cataggctgg gcgcagtggc tcacgactgt aatcccagca ctttgggagg  92220 

ccgaggcggg tggattacct gaggtcagga gttcgagacc agcctggcca acatggtgaa  92280 

accccatctc tactaaaaat acaaaaatta gccgggcctg gtggtggaca cctgtaatct  92340 

cagctactcg ggaggcagag tcaggagaat tgctggaacc tgggaagcag aggtttgatc  92400 

gctccattgc acttcagccc aggcaacaac agtgagactc cgtctcaaaa aaaaaaacaa  92460 

aaaaaaaaac aaaaaaaaaa gagaaacaaa gggcatagac atagagcaca aaaatctctg  92520 

tgaatttcca aaagccaaag ttcacacctt cttatttgcc attaactgcc agtttcttcc  92580 

tgactcagtt aaacatccaa ggcctctaac tgaatccaag tcagttaatt atcagatcca  92640 

gtctgattct ggacctggtc cagtttctgt catgacttct gaacccattt cagattttaa  92700 

aatttgctca aacaaattca gataactcaa aacacaaatc catggagctt cagaatctga  92760 

gagcttaccc acaatcccca gttgctgcaa gagaggaatg gacacagaga gtctgactgg  92820 

taccatgctt cgtcactcag tgcttctggg gattgctaga ggttctactt cggatcccac  92880 

ttctgacacc atctgttaaa agaaaaacta gacaaattaa atttaacaga gtttaattga  92940 

ggaaacagtg attcacaaat caggcagccc ttagaaccag aataggttca aagagactct  93000 

ggcactacca catggttgaa gacttatgta cagaaaaagg aaagtgatgt acagaaaatg  93060 

aaactgaagt acagaaacag ctggattgct tacagcttga tacttgcctt atttgaacat  93120 

ggtttcaaca gttggctgca ttttattggc tgaaactcag caattggtac aagaataggt  93180 

tacagcttgt ttacacgtcc ggagattacc attcactatg tacagagaaa cctttaggcc  93240 

aaactttaaa aatgtaacga gacagcttta ggtgaaactt aatgtaacac tacctaccag  93300 

gtgaggatta actaagatcc ttatttttct gttgaggatg ttgaaggagt ggttaaactc  93360 

cttgtttcag tttccttact ttccaaaatt tgcctttcat ctccaccact ttttctctct  93420 

tcttcagatt ctgtccttca acttctaagt gtgcaaaaat cttcagttca gtttcttttt  93480 

aatcagcaat tttcacatta cctaacaatc tcttaggctt ccagacctcc attctctccc  93540 

ctcccttgaa atcatagtgc tctgctaaaa ctggttcctg gaagatttcc tgtaccttta  93600 

tgcttagcaa gttcaatggt ctcttcttag ccattatttt tctcaaaatt tgactgactc  93660 

cttttttttt tttttttttt tgagatggga tctcactctg ttgcccaggc tggagtgcag  93720 

tgatacaatc acaactcacc gcagccttaa cttcccaggc tcaaacgatc ctcccacctg  93780 

agcttcctaa gcagctggga ctacaggcat atgccaccat gcccagctaa ttttgttttt  93840 

ttgtatagat aggatctcac tatgttgcct agactggtct cgaactcctg gacttaagca  93900 

gtcctcctgc cttggcctcc caaagtgctg ggatcatagg tgtgagccac cgcactctgc  93960 

cgaccttctt gacatcctcc tctcttgcct tctggttctt tagtttacgt tttctggctt  94020 

cttttccttt tcattatcta tctgctctcc tttgggattc tgacacagtc tcaggggttt  94080 

ctgctgtcac gcttgtttga gaaattcggc tgtcatgaaa gaacaccacc tctatttgtg  94140 

acgaaagcta ctctgaaatg tttagtcttc tctttgacta agagtgacat tcaaaattag  94200 

tatgacattt atttctttat tttattgaga cagagtctca ctctgtcatc caggctggag  94260 

tgcaatggcg tgatctcggc tcactgcaac ctctgcctcc caggttcaag cgtaaaatca  94320 

gtatgacatt tcatatcttt caccagtctc ttaagtcctt tatcattact ccattttcat  94380 

atattctggc caaagaaact gaagcatcgt attccttcta tctccctggc ctttttaacc  94440 

tgtttccact catgctgccc tttactgaga atgcctcctt cctatctcta cccatcagta  94500 

tcctctctat ttgtgcttgt cagtttttgt gcaaaataca attgtattat aatgattttg  94560 

taaatgtatc atccctctgg aatctaattt tcttgaagaa atgatcctta tctaatttaa  94620 

atctctactt atataaagta tgtcaacaat gaaacattct tgagtgatac agagaccagt  94680 

ttacctcagg ccatttcaga atttgccttg ccttcttcat ggcaagaaga aattagaata  94740 

tgagaaataa aatttttttc tatttaattc tgttcatccc tttttattaa tcccaaatct  94800 

ctaaatggat gctttaatga tcacttaatg tatttttttc ctccagagtt tttatccccc  94860 

tgctttcaag tgaaatgtca caaggatggc ttattacaat gctatgatta tcttatttgg  94920 

ccttgaaagg ccaaaaaaaa aaaaaaacaa aaccatttcc aatgtttttc aaacttgagc  94980 

ttttttattt ttcattttat atttgttatt cgcagcttga atagatgtct cagaatcatt  95040 

gggcttgtgg ctcttgttag gctaagtgaa aatactcaat ttcatacttc tttaattaag  95100 

caccgataag gaataggaga aacttcatct ctatcctgaa ggaatcagag tgttttgggc  95160 

aaagatcact cagatccttg acttaggacc tcaattgttt taaaaaacca gtgaagcgat  95220 

tgttgctcat tattgcttat ttatactgaa ttcaaaattt tctataaata tgaaattggt  95280 

ggccgggagc agtggctcat gcctgtaatc ccagcacttt gggaggccga ggtgggtgga  95340 

tggcctgagg tcaggagttc aagaccagcc tgaccaacat ggtgaaaccc catctctact  95400 

aaaaatacaa aaattagcca ggcgcggtgg cacatgccta taatcccagc tacttgggaa  95460 

gctcaggtgg gaagatcatt tgagcctggg aagttgaggc tgcaggagtg agttgtgatt  95520 

gtatcactgc actccagcct gggcaacaga gtgagactcc acctcaaaaa aaaaaaagaa  95580 

attggttttg ggggtttttc agtgtaaatc aaagtacatt aaaatgctgc ctgcctcatc  95640 

tgtttatttg gagacaagag tctcactctg tcacctaggc tggagtgcag tggcataatc  95700 

ttagctcact gcaacctccg cttcccagat tcaagtgatt ctcctgcctc agcctcccaa  95760 

ggagcaggga ctacaggtgc ctgccaccac accagactag tttcgtattt ttagtagata  95820 

tgggttttcg ccatgttggc caagctggtc tcgaactcct gacctcaagt gatcctcctg  95880 

cctcagcctc ccaaattgct gggattatag gtgtgaggca ctgcacccag cctcatctgt  95940 

ttttaaattt tgtttttata ttttaaaaaa atcctctgag ggcataatct ttcctgctat  96000 

cctagtgtga gataggtaat actatagaaa ttctggctct accatttgtc taatcatttg  96060 

aactttggcc aaatatgtaa tgtctatgaa actattttct gatctgtaaa acaggaataa  96120 

tacctgccgt gcctctttct tatgaatctt gtgagatcaa attagaaaat aaacaatagc  96180 

taaaatgtat caagttttta ccatggtcct ggatggtgtg ctaagtgctt tacatatatg  96240 

atctcattta atcttcacac caaccctata gttgaagcaa tccttttaca gatgaggaaa  96300 

actgaagtaa gtgcctaaaa tttcatagta gtatgtagca gaactgggaa tggaactctc  96360 

catactaact ctagagctga gctcttaacc agcatatact attagtaatg ctccttgtaa  96420 

actacagaat gccgtataac tgtatagaat gttcttcatt tgcaaaatgg attactgaca  96480 

gaccattacg cttaacatca gtagtctggt gacctctcat atatgaagca cacaaatctt  96540 

tgcttcatcc ttccattccc ttcccaaact tcccattact actttgtagg aattcatgac  96600 

tagacaaagg ttttatattt agtggtttct ccttccaggg gtttcacaga ccagctgcgt  96660 

aagatttcta aggatgcagg gatgcccatc cagggccagc catgcttctg caaatatgca  96720 

cagggggcag acagcgtaga gcccatgttc cggcatctca agaacacata ttctggccta  96780 

cagcttatta tcgtcatcct gccggggaag acaccagtgt atggtaagga tatcttaaga  96840 

ctgcattttt cctcaagtac ttgatgtcct tttaggatta tactgaaaca tatcctaaaa  96900 

ctttcaaata ttaaaatata ttttatgata cagtatttaa aaccatgtat tattacttga  96960 

agacaaatta atatagcaaa ctaaatagtc caagatgaga cattgtaaaa agagtttccg  97020 

ggctgggcgt ggtggctcac gcctgtaatc ccagcacttt gggaggccga ggcgggtgga  97080 

tcacctgagg tcaggagttc gagaccagcc tggccaatgt ggtgaaaccc catctctact  97140 

aaaaatacaa aaaattagct gggcgtggtg gtgggcgcct gtggtcccag ccactcagga  97200 

ggctgaggca ggagaatggc gtgaacccag gaggtggagc ttgcagtgag ccgagatcgc  97260 

accggtgcac tccagcctgg gcgacagagc gaaagtccgt ctcaaaaaaa aaaaaaaagg  97320 

gtttcagtag tgaaaagagg cattacataa caatggctaa agaaagaatt attgaataaa  97380 

aatggcattg agataatttg agtatcagta taatgtagtg gttaaaagca caggctatca  97440 

aattaaactg tgttgctcaa tattcaggta ctgccggttc tactacctgt gtgatttggc  97500 

tgaattactt aatcacacta gcccttagtt tcctcatctc tggaattggg acaatattta  97560 

tgtatgtatg tggtgtgtat gtatgggata ggatctctct cactctttca ggctggagtg  97620 

cagtggtgca atcatggctt actgcagcct tgacctcttg ggctcaagca atcctccttt  97680 

ctcggcctcc caagtagctg gaactacagg catgtgccac cacactggac taatttttta  97740 

tttttttatt ttttttgttt gtatttattt atttatttat ttttattata ctttaagttt  97800 

tagggtacat gtgcacaatg tgcagtttag ttacatgtgt atacatgtgc catgctggtg  97860 

cgctgcacac actaactcgt tatctagcat tagatgtatc tcccaatgct atccctcccc  97920 

cccccccacc ccacaacagt ccccagagtg tgatgttccc cttcctgtgt ccatgtgttc  97980 

tcattgttca attcccacct ataagtgaga atatgcggtg tttggttttt tgttcttgcg  98040 

atagtttact gagaatgatg atttccaatt tcatccatgt ccctacagag gacatgaact  98100 

catcattttt tatggctgcg tagtattcca tggtgtatat gtgccacatt ttcttaatcc  98160 

agtctatcat tgttggacat ttgggttggt tccaagtctt tgctattgtg aataatgccg  98220 

caataaacat acgtgtgcat gtgtctttat agcagcatga tttatagtcc tttgggtata  98280 

tacccagtaa tgggatggct gggtcaaatg gtatttctag ttctagatcc ctgaggagtc  98340 

gccacactga cttccacaat ggttgaacta gtctatttat ttttttgtag agacaggatc  98400 

tcactatgtt tctcgggttg gtctcaaact cctgggctca agcaatcctt aaaccttggg  98460 

ctcccaaagt gcagggatta caggtgtgag ccactgcacc tagcctcttt ctggttttaa  98520 

ttgagcattt tatatgattc tattttcttt cctcttttag tgtatcagtt atacttcctt  98580 

gatatatagc acacataccc tgggatacta ataataccta atccatatat agggttgttg  98640 

taaggattaa ctgagtctaa tatgtaaagg gcctagaata gcacctgtca tatagtaaac  98700 

agtcaatgtt aactgttatt attataaaca aaattttgtg agattaataa gctaaatata  98760 

aatcattgaa tcgtagaaaa atacaaagaa aatataattt tcaaaccact gaacggggta  98820 

aaatcatgta agtttagaaa taatagaaga aatcacaaaa gaaaattgtc agatttgact  98880 

gagtactgag taaacattaa attttctctt tctttctttt tttttttttt tttttttgag  98940 

agagagtctc gctctgtcgc ccaggttgga gtgcagtggt gcgatctcgg ctcactgcaa  99000 

gctctgcctc ctgggttcac gccattctcc tgcctcagcc tcctgagtag ctgggactac  99060 

aagcacctgc caccatgtcc agctaatttt tttgtatttt ttagtagaga cagggtttca  99120 

ccgtgttagc caggatggtc tcaatctcat gaccttgtga tcctcccgcc tcagcctccc  99180 

aaagtgctgg gattacaggc gtgagccacc atgcccggcc cttttttttt tttttgagac  99240 

agagtctccc tctgttgccc aggctggagt gcagtggcat gatctcagct cactgcaacc  99300 

tccacctccc aggttcaagc tgttcttctg cctcagcctc cctagtagct gggtctatag  99360 

gcgcgtgcca ccatgcctgg ctaatttttg tatttttagt agagacaggg tttcaccatg  99420 

ttggccaggg tggtctcaaa ctcctgacct caggtgatct gcccacccca gcctcccaaa  99480 

gtgctgggat tacaggcatg agccactgcg cctggcccct aaatttccta catgtcacgg  99540 

atgtactaaa atgaaaagaa aaccaataga gtgtggaaaa tatttgtagc aaatagaaac  99600 

aataaacaaa tagtttatta ttagttaaat aaaaaccttc tttttttaga ttaatgagaa  99660 

aagattataa actgaaattt agtaaaaaca aagcaagtaa atatatgata agtttgtttt  99720 

tattcatagt taaagaaaaa tacaggccag atgcagtggc ttatgcctgt aatcccagca  99780 

ttttgagaag ccaaggtggg cagattgctt gagttcagga attcaagact agtctgagca  99840 

acatggcgaa acctcatatc tgcaaaaaaa tagaaaaatt agccaggcat ggtagtacac  99900 

atctgtggtc ctagctactt gggaggctga gataggaaga tcacttgagc cagtaggtgg  99960 

aggttgcagt gagccaagat catgccactg cactccagca gcctgggcaa cagagcgaga 100020 

ccctttctca aaaaaaaaaa aaaaagagag aagaaaagta caaatcaata aagggaaaaa 100080 

ttttgtgctg ctaaattagc aaacatattt aaatattata atacctagtg cttgtgagta 100140 

tgcagtgtat taatacgttg ctgatggtag tataaattga tattaccttt ttcatcaaaa 100200 

ctgtaaacat gcctgggctg gtctcgaact cctggcctca agtcatcctc ccgcctcagc 100260 

ctcccaatgc tgggattaca ggcatgtgcc actgctcctg gcccctcctg gttttaattg 100320 

agcattttgt ataattctat ttttcattct cttttaacat attagttaga cttcctttaa 100380 

aaatttttgt agtgttttcc ctagactttt taatatatat ttacaactaa tctgagtcta 100440 

cttttaggta acattatacc acttcttaga tagtatagag ataccttgta acagaatact 100500 

cccaattttt cccttctgta ccttatattt ctgtcattta tttcacttat ccataagcta 100560 

taactaccca atacactgtt gctattacta ttttgaacaa ataatcatct attagctcaa 100620 

ttaagaatat gaaaatacaa gattttattt tacctttatt tatttgctga ccttcaacct 100680 

tcctccttac ttttgttttg ttttgttttt tagagacagg tcttgctatg ttgcccatgc 100740 

tggtcagtgg ctattgtcag gcatgaccat agtgcactgc agccccaaac tcctgggctc 100800 

aagtactcta cccacctcag cctccccagt agctggtact acaggcatga cccacactgt 100860 

accctgcttt tccttcattt atgatttctg atctgtatca ttttccttct ctctggaaaa 100920 

ttcttttaat atttcttgcc aagcatttct accagcaaca aataccctgt ttttatttgt 100980 

ttgagaaact ctttatttct ccttcatttt tttttttgag ccacataatg atttaatgtt 101040 

tacttgcaaa tcattcactc acataatttc aagtactaag tcattctgga attcttacat 101100 

tctgacatta agaacattca catgttgtgc agccatcatc actatccatt tccagaactt 101160 

ttttccatca tcccaaactg aaactcttta tccattaacc aataacttta atatcctatt 101220 

aaacctcacg taacccctgg aaagcactgt tctactttcc gcttccatga atttgactat 101280 

tctagtttcc ttatgtacat gagtcctaca atatttggct tttggcataa tatcctcaag 101340 

gttcatccat gttgtactat atgtcagaat tttcttcctt ttttgggcca aataatattc 101400 

cattgtttgt atatgtgtgt gtgggggggc ggggggtgtg tgtgtgtgtg tatacaccac 101460 

atcttgttta ttcttctgtt gatggacact tgggttgctt ctacacttta gctatcatga 101520 

gtaatgctgc tatgaacata ggtgtacaaa tatctcttca caaccctgtt ttcagctatt 101580 

ctgggtatac atctaataag tgtcattgct gcatcatatg gtaattctat ttttaatttt 101640 

ctgaggaacc tccacagtgt tttccacagt ggctgcacca ttttacatgc ccaccaacag 101700 

cgcacaggag ttccagtttc tccacatcct tgccccaatg tttgttattc tctggctttt 101760 

tgatagtagc catcctaatg ggtgtgaagt ggtatctcat aatgtctttg attttgcatt 101820 

ttcctaaatg attagagacg ttgggcatct tttcatgtgc ttatgggtca tttttctgtt 101880 

tatcttcttt agagaaatgt gtattgtcat ttgtcctttt ttttaaggca aggtctcact 101940 

ctgtcaccca gactggagtg caatgacacg atcatagttc actgcagcct ccatctccta 102000 

ggcccatgca atcctcttgc ctcagcctcc tgagtagcta gaactaaaag cacataccat 102060 

catgcctggc taattaaaaa aaaaatttgg cagggatggg gtcttgattt gttgcctaag 102120 

ctggtctcta actcctgggc tcaagcaatc cgcctcagcc taccaaagtg ctgggattac 102180 

aggtgtgaga cattgcaccc atttttctat gttttttata tataagaagt tatgctgggt 102240 

gcagtggctc acacctgtaa tcccagcact ttgggaggcc aagacgggtg gatcacttga 102300 

ggtcaggcgt tcaaaaccag cgtggccaac atggcaagac cccatctcta ctaaaaatac 102360 

agaaattggc tgggcgtagt ggctcatgcc tgtaatccca gcactttggg aggccaaggc 102420 

gggtggatca cctgaggtca ggagttcaag accagcctgg ccaatgtggt gaaactccat 102480 

ctctactaaa aatacaaaaa aaaaaaatta tcagggcatg gtggcaggtg cctgtaatcc 102540 

cagctacttc aagaggctga ggcaggagaa tcacttgaac ccagaaggca gaggttgcag 102600 

tgaaccgaga ttgcgccgtt gcactccagc cctgggcaac aagagcgaaa ctcttatctc 102660 

aaaaataaaa aataaaaaca aaaaaaataa aaagtaaata aaaatacaga aattagctag 102720 

gtgaggtggt gcacacctgt aatcccagct actcgggagg ctgaggtagg agaactgctt 102780 

gaacccagga ggcagaggtt gcagtgagct gagatcgcgc cactgcactc taccctgggt 102840 

gacagaatgt gactccatct caaaaaaaaa aaaagaagtt atggctgggt gcagtggctc 102900 

ttgcctgtaa tcccaacact ttgggaggct ggagcaggag gatcacttga gcttaggagt 102960 

ttgagaccag gctgggcacc atggtgagac ctccctcatc tctacttaaa taaaaaaaaa 103020 

aaggcttggt gtggtggtgc atgcctgtag ttccagccac ttgggaggct gaggcaagag 103080 

gatcgcttta gctcaggagg tcgagactac agtgatgcat gatcatgcca ctgcactcca 103140 

gcctgggtga cagagtgaga tcctctcaaa aaaaaaaaaa aaagttatat acaccgaaat 103200 

atttatgatg gttataatgg cagaggagag gaaaggaaca ggggactttt gttctttgcg 103260 

ctataatacc tctgaatttt taaattaaag ataagagaat aggattgaaa gctgtaagtg 103320 

tactgtgatt acaagtacat taaaataata taaatgagaa aattattgga agagagtact 103380 

ataaaacgat aacaagggat tatgtgcatg tttcacttta tgcttttcag ttattgcagt 103440 

tatgctatgg caaaaatata cctttttata caaagaagaa aacaactaga aaaattgtca 103500 

ctaaatactt aagctagtct tcaaagcagt atactttcaa ttttaacagc atcgccttag 103560 

tactgtattg gcataatttt tggtatcctg taatacaatg atggatttta agggggaaac 103620 

atagtagctt tattttcagt atgtaaaatt attttcaggt ctttttttct gactagaggt 103680 

tttgcatcta ttccatagcg gaagtgaaac gtgtaggaga cacacttttg ggtatggcta 103740 

cacaatgtgt tcaagtcaag aatgtaataa aaacatctcc tcaaactctg tcaaacttgt 103800 

gcctaaagat aaatgttaaa ctcggaggga tcaataatat tcttgtacct catcaaaggt 103860 

aagatatgct aatcgcttat gaaaatatta tttttatatc ttcatttgtc tatatatgac 103920 

catatctaac tactataagg gctgtgtaag agaccccctt aataattcct actatgggag 103980 

attcgtagac attttggtaa aaaaataatt tggattggca aggttcagag attctcttgt 104040 

gaaaatgccc cccacaattt tattttatct tattttttaa ggaaagaatg aagcaaagca 104100 

acaaaagcag agatttactg aaaatgaaag tacactccag agggtgggag caggctcaag 104160 

ccccaaaaat tttcatttag tatgcaaagt acctcttacc tagccagaaa gtatccagtg 104220 

ctttatttct cactggagag cccagcttga agaattttca ctttatttgg taatcatctt 104280 

caacctggtt tcatgagact actcacctac ctggaatgtg aaggagagaa ggaactggga 104340 

gcccagatta gtcaattaag taagccatat cagccttcct gctatagtca gtgagaaaac 104400 

acattactgt tagatcaccc ttcttagagc tggagctctt aggaagtaag agacaacatg 104460 

acctagaaac aggaggtagc ttattgtgca agtcactgag gaagaggtca tttttcagag 104520 

aattgaacaa gttccctttt aatagttgaa gcaattaggc ctcaaaaaag ttaactgtac 104580 

accacaaata aacattagaa taagaattgg cccatgtttg tttgacacaa aagtcctttt 104640 

tttcctgttt ttccatgcca tctctacttt ctacccctgt taaatatgag atgagatccg 104700 

taaatgagat aaataaagaa ttttatcaac aagcccaaca tggtgaaact ttatctctac 104760 

aaaaaaatag aaagattagc catgtgtggt ggcatgtgcc tgtcgttcca gctactccag 104820 

aggctgaggt gggaggatta cctgagccca gggaagtcaa ggctgcagtg aactgtgatt 104880 

acgccactgc actccagcct gggcaacaca gtgagaccct gtctcaaaaa aacaataata 104940 

acataaagta aaataaaagg aagtcctagc ttcctttatg accattgaat atatgttact 105000 

caaatttata cttttggcca gggagtggga gtagtggatt cccaaaatcc cttccagtct 105060 

gaagtgtaat gattcctttt tcccttgaga gattacatag gtttaaaata taagtctttt 105120 

tttaaagagt gataaaaatt tgtggatcat aaggaagttt ataattttgt gcccatgttg 105180 

gagaatacta gcatctgtta atattaatac agcccttttc aaccaccagc accactattt 105240 

tagataaaat tctgctgtga ataaaacttt ggattggccg ggtgcggtgg ctcacgcctg 105300 

taatcccagc actttgggag gccaaggcag gtggatcaca gggtcaggag atcgagacca 105360 

tcctggctaa catggtgaaa ccccatctct actaaaaaat acaaaaaatt agccgggtgt 105420 

ggtggcgggc gcctgtagtc ccagctactt gggaggctaa ggcaggagaa tggcatgaac 105480 

ttgggaggtg gagcttgcag tgagccgaga tcgtgccact gcactccagc ctgggtgaca 105540 

gagcgagact ccgtctcaaa aaaaaaaaaa aaaaaaaatt tggattacat aggacttcct 105600 

ctgtgctgtc aataacttga agttacgttg caattgtgtg aaacagataa atggatactg 105660 

aaaaaatgaa atatctaacc ctttttcaaa atgtgtttaa gaccttctgt gttccagcaa 105720 

ccagtgatct ttttgggagc cgatgtcact catccacctg ctggtgatgg aaagaagcct 105780 

tctattgctg ctgtgagtgt tagccaggtt tatcttacct aaggttgaca gaccagtatc 105840 

aattttgcag tttcaacttt ttgaatttta atattttctt tgtagccaac tttcataaat 105900 

gttctttggg tttttgaaaa gaatgattat tctctggttt ggagtttgga agttccatat 105960 

gtatctatta aatcaagttt gctagttata ttattcaaat cttctgtatt atactttaat 106020 

ttgtctactt gacctctcca tgattatgca tttttagtta ctttttgttg ttttgaatag 106080 

tttgtttgta tatttcagta atgtctttgt catagaaaga tacactacat ataagcttgg 106140 

tggattacat tttttatata taaaatgtct cccaccttca tccaggtcaa tactttgcac 106200 

ctgaattctt ttattttatt ttattttatt tatttttttc agacaaagtt atcttgttgc 106260 

ccaggctaga gtgcaatgac acaatctcgg ctcactgcaa ccttcatctc ccaggttcaa 106320 

gcgattatcc tgcctcagcc tcccgagtag ctgggattac aggcacctgc caccatgccc 106380 

ggctaatttt ttgtactttt agtagagacg gggcttcacc atgttggcca ggctggtctt 106440 

gaactcctga tctcggtcag tccacctgct tcggcctccc agagtgctga gattacaggt 106500 

gtgagctacc gtgcccagcc aaattcttta ttttactact gccactcctg tttttaacat 106560 

ctgcctgtta tttctttgct ctctgtgttt gtaacctttt tgtctcagtt taagtgtatt 106620 

tcttataaac ttgagaaagc ttgataatat tttacctatt ttgaaaatca cttgatttta 106680 

acaaatagcc aacatttcga aaatatgaac atcttttagg catatttaat aaacttcaga 106740 

aattaaactg taagatttaa ttggccaggc gcggtggctc acgcctagaa tcccagcact 106800 

ttgggaggct gaggcggggg tggatcgctt gacgtcagga gttcaagacc agcctgacca 106860 

acatggtgaa accccatctg tataaaaaat acgaaattag cctgtcgtgg tggtgggtgc 106920 

ctttaattcc agctattcgg gaggctgagg caagagaatc acttgaactc gggaggcgga 106980 

ggttgcagtg agctgaaatc atgccactgc actccagcct gggtgacaga gggagacccc 107040 

atctcaaaac aaaaaaaaag atttaatatt ttttctatga tacattataa tcttcacata 107100 

aatcttgttt tatgaatctg ataaatctaa ttcatccctg aaaatgatag taatatttaa 107160 

atttccactt catgatttca aaactatttt cattagtaaa ggaaattaat ttttatctat 107220 

taattctctt gcttttgtat ttttaatgtt atacatgaat tattttcttt aaatgttcag 107280 

tggttgtatt gagtcatctc taacattcat taaagtgttc ttatagatga taaaatgata 107340 

aagaaaggaa ctcaaaagac ttccttggat ttgctacttt gggtcatttt ccacaaaggt 107400 

ttaagcatat tttaattcct ttggacttct ggtagtcatt gtctttttct actaaatccg 107460 

tttctaccaa atacccactt tcttttgtgg ttctcagaag tcttgtaaat agaatttatt 107520 

ggttgattct ttttcactat atggcttcta tctccaagaa cttagagagt agtgtgagaa 107580 

actaagtaag taatgagtgc cacatagtat aataggtgtt atcatgataa cgaagtaaca 107640 

acatttaagt tgcaagaacc tggtgtgttt tgggaatgtt gagaaataca aggaattgga 107700 

acatagtata ctgcaggcta tgaggctagg aagcctttgt gaggcatttt gttccatccg 107760 

agggtctgga tttattcttt tttttttttt tttttttgag acagagcctc gctctgtagc 107820 

tcacgctgga atgcagtggg cgcgatcttg gctcactgca agctccgcct cccgggttca 107880 

cgccatcctc ctgcctcagc ctcctgagta gctgggacta caggtgcacg ctgacacacc 107940 

cggctaattt tttgtatttt tagtagagac ggggtttcac tgtgttagcc aggatggtct 108000 

tgatctcctg accttgtgat tcgcccacct cggcctccca aagttctggg attacaggcg 108060 

tgagctaccg tgcccggcct ggatttattc ttaagtagcg agataccttt caagggaaag 108120 

aaatggtcaa agttccattt ttgaagcatg actttggtat aggttaactg gaagaaaggg 108180 

tctggaggca gtgaccagct ctaggctctg atcagaataa tgttataagt tcatgctttg 108240 

aggtctcttc tccaaagaca taacaatatt agacacagaa agagaaatta atatagctag 108300 

tttcaaaacc aagattaact tctctgagga ccagatacag aacacaaatg cagctcaata 108360 

agactgtata gattcaggcc aagagggaaa attctgattt taaaatttat gaagcgtaac 108420 

agttctaaga tgaagctaaa gtcttaagta tggcttctga gataggttgc taaagtggaa 108480 

gagataggaa gaaaaatcag tggtttgaat tggtccttgt tttttcttat ttcttttctc 108540 

ttattctctt atacacatct ttttgtcttt ttctttcctt actaatcttt aagtctacca 108600 

acaacacaaa gaatctaatt gttaaatgta tagttcagcc tagttatagg aaaatagttt 108660 

tttaccctat actaggtgtt ttattctgtt cttcaacggg aagtactatt ctttttaatt 108720 

ttttaaaaag atggggtagg ctgggtgcgg tggctcatgc ctgtaatccc agcactttgg 108780 

gaggccaacg cagacggatc acgaggtcaa gatatcaaga ccatcctggc caacatggtg 108840 

aaaccccatc tctactaaaa atacaaaaat tagctggggg tggtggtgca cacctgtagt 108900 

cccagctact ctggaggctg aggcaggaga atcgcttgaa cccaggaggt gcaggttgca 108960 

gtgagccgag attgtgccac tgcactccag gctgatgaca gagcaagact gcgtctcaaa 109020 

aaaaaaaaaa aaaaaaaaaa agagagaaag agagagagat ggggtcttgc tattttgccc 109080 

aggctggcct taaattcctg ggcacaagtg atcctcctgc ctcagcttcc tgagtagctg 109140 

ggactatagg cacatgccgt catacccaac tcagaattac tatttttgat tactttcaaa 109200 

gtaaacagtg atgaacaggt tacagtaaaa taaaaatgta aatgaaattc atgtaatttt 109260 

gattatcatt tatttttatt tatttattta tttattttac tttttctaac ctaggttgta 109320 

ggtagtatgg atgcacaccc aagcagatac tgtgccacag taagagttca gagaccccga 109380 

caggagatca tccaggactt ggcctccatg gtccgggaac ttcttattca attttataag 109440 

tcaactcggt tcaagcctac tcgtatcatc ttttatcggg atggtgtttc agaggggcag 109500 

tttaggcagg ttggttacct agaatctcat cagactatgg tgaaatcaga tattgtgttt 109560 

ataatatggt gtctagttct agagttaaaa accttgttag agttccccaa gtcaaaactt 109620 

ggtgttttgt tagattgtct ttttgaaaat gttcactacg aatgtgtatg ccttgcttgc 109680 

taagaccatg ttctaataat cgttaaaatg gaatctatta gctatagagt ggtgaaatta 109740 

aggaatcctg agattaaatc attatcctac tttgaagtat ataaaaacaa atagctgact 109800 

atattgaatc tttccatttc atattctcta ggtattatat tatgaactac tagcaattcg 109860 

agaagcctgc atcagtttgg agaaagacta tcaacctgga ataacctaca ttgtagttca 109920 

gaagagacat cacactcgat tattttgtgc tgataggaca gaaagggtaa tctcacctct 109980 

gttgtaatac tgttataaac caagcttatc caacatagtt catagagcat tcaacaaggg 110040 

ccctctgcca acagcaggat ttccaatata tagtagcaaa tttcaacaat tacattatga 110100 

gtatagaagc atcaaaatag attattttta actttctaga atttctagtc acactccaaa 110160 

tattcaaaat ctcattctac ttttttgttg tgaagaaact catggtttta aaattattct 110220 

tctattcata ttttcctaaa atcttcagaa aaaacagtac attctctttt taaaatatct 110280 

catacaaatt agttttttaa aaaagtggaa attcaggcca ggcacagtgg ctcacacctg 110340 

taattccagc accttgggag gccaaggcag gcagatcact tgaggtcagg agttcaagac 110400 

cagcctggcc aacacggtga aaccctgtct ctactaaaaa tacaaaaaat agccaggtgt 110460 

ggtggcgcac atctgtaatc ccagctactc gggagactga ggcaggagaa tcacttgaac 110520 

ccaggaggca gaggttgcag tgagccgaga tggtgccact gtactccagc ctgggcaaga 110580 

gagcaaaact ccatctcaaa aaaaaaaaaa aaaaaaaaag tggaaattta tacaaactaa 110640 

cttttagcca tgtttccttt aaagttcaca gaattatttt atgcatttta taatgtgaat 110700 

gtatattttt tataattagg aaggaaagag aggtataaat acctaaggaa atatgttttc 110760 

tttttttttt tttttttttt ttttgagacg gagtctcact ctgtcgccca ggttggagtg 110820 

cggtggcgcg atctcagctc gctgcaagct ccgcctccca ggttcacgcc attcttctgc 110880 

ctcagcctcc tgagtagctg ggactacagg cgcctgccac catgcccggc taattttttg 110940 

tatttttagt agagacaggg tttcaccgtg ttagccagga cggtctcgat ctcctcactt 111000 

tgtgatccgc ctgcctcggc ctgccaaagt gctgggatta caggtgtgag ccactgcgcc 111060 

cggccagaaa tatgttttct tatctgtgtg cagcaagaca gcagtcttac tgtcattttc 111120 

agtgctctga tcacatctgc ccccatcctg taaatcttgg agcagagaaa tctaatgata 111180 

ccaagtgttg tttccccttg agaaagggat ttgatagaaa ggactaagag aggggtgttt 111240 

ttctttgcca tacatactca ctgtattcct ttgggcaagc aacttaacat ctctgtgtct 111300 

gtttatttct tagcaagatt ggataatatt aatatctacc ttatttgggt tgtcgggaga 111360 

attaaataaa atacgtaatg cacttagaac agggcttggc ccacactaag tactcagtaa 111420 

agattggcta gctctcatta gtagagtgat gagaacaaaa aaaaattaat aaataaagtt 111480 

tggctagctg cagagtggtg gtgatagtgg tagaatagag aagaagaaat aataatagat 111540 

attgttctaa gtattgctta taaatttcat caatttaatc ctcaccaaca agattatgag 111600 

atagttgtat ttttttgttt ttgttttttt tgacagtttt gctctgttgc ccaggctgga 111660 

gtgcagtggc atgactttgg ctcactgcag cccccacctc ctgggttcaa gtgattgtca 111720 

ggcctcagcc tcctgagtag ctgggattac aggcatgtgc caccacaccc ggctaatttt 111780 

tgtagtctta ttagaggcag gatttcacca tgttggccag gctggtcaca aactcctggt 111840 

ttcaaatgat ccgcccacct cggcctccca aagtgctagg attataggtg tgagccatca 111900 

cacccagcct acaacttttt gtatatatta attagaagat ttacgtgttg ctaatttatt 111960 

agagttaagt atttttttag gaccaggcat aatttagtag attatgaact gttttgtttt 112020 

gtgcttggta aagtgaagct ggttggtcca caccactata attcaaggta ctaccttata 112080 

acagtcactc acgtggcaaa aatattatct gagtcagtaa aatagtttct gatttgctag 112140 

ccttgtaaac ctagacttac agttaatgat tttaaatgtg ttgggataag gcggtggagg 112200 

tgggtataat aaacattttt aagtgtttta taaggagctt gtatcatcaa gaattttggg 112260 

tcatttcagt tatattatat ccactcagag aaaatcatgg tgtcctctta caagatgttg 112320 

aaactgatag tatgaaataa aaggaataag gcctttgcaa ttatttcatt gtttgaatcc 112380 

cagttctgcc ctttattgtg tgctattgag caaattattt tgtattcctg agcctttatt 112440 

tccctaaaca aatggaaata atccctaact tgcaggattg ttaccaggtt ttagaaataa 112500 

tgtgttcaaa gtgcctgatc cataaatggt taacaaatgg tgtgactgtt gttgatcttg 112560 

tcagcattct ctctctctaa acatctagtt ttctccaagg taaatgctga tcttcataaa 112620 

tcacacgttc aagaatacct actatgcaca ggtaccataa attggagcac tttaagttaa 112680 

tttaaaaaaa atttttttta gtgtcttcca cccatagtgg ggtcaactat cagctaagca 112740 

gtagtagaga ctgtattagg ttttgttgtg tatcagcgct cactttcagc aacatgtaag 112800 

aataggaact aggacctgcg tagtctgctc tgaatgactg cttaagtcat atttcaaggt 112860 

gaaagtagtg aaatgtagga tcagcctatg tattcataca ttttttaaag tgctttcaga 112920 

tatattttta cctttttctt gtttgtttaa actttaacca aacaaatcta ggttggaaga 112980 

agtggcaata tcccagctgg aacaacagtt gatacagaca ttacacaccc atatgagttc 113040 

gatttttacc tctgtagcca tgctggaata caggtaagcc tacactttgg gtaaaatatt 113100 

ttaattcaag aactgtcatt cttacgtgta ttttttaaat ctcagaaaaa ggataaagaa 113160 

atactctttg cattccaaat tgtttccaca tgaaattaga tgaaactttc agtaaacaaa 113220 

tgtcttccct ttccttacct tgagaggggc ttaggaactt atttttatga aaataccaga 113280 

atataagtag tttaatagaa tgaatctccc taaaacaggc ccttaatttc actaaaatgt 113340 

taaaaaatgt gaaagtacct gattgttcct ttagcatatg catctttaaa aaaaaaagag 113400 

agagagagaa agagaaagca ctattttgct caggctagac tagaactctt gggctcaagc 113460 

agtcctccca cctcagcctc ccaagtagtt gggacaacag gcctccacac tcagctaatg 113520 

acgataacat tttatagaaa actttgacat gtactagtag tattaagcat gtgaaagagt 113580 

ttaattgggc tgggcatggt ggctcacgcc tataattcca acactttggg aggctgagat 113640 

gggcagattg cttgagttca ggagtttgag accagcctgg gcaacataga gaaaccccgt 113700 

ctctacaaaa aatataaaaa ttagccaggt gtggtagcac gtgcctgtag tctcagctat 113760 

tcaggaggct gtcgtgggag gatcacttga gcgcggaggc agagggaggt tgccatgagc 113820 

caaaatcatg ccactgcact ccaggctagg tgacggagcc agaccttgtc tcaaaaaata 113880 

aaaaaaaatt taattgtaga attacagctt tagttttttt ttgttgttgt tgttgttttg 113940 

ttttgtttgt ttgtttgttt gtttttgaga cagagtctca ctctgttgcc caggctggag 114000 

tacagtggca tgatctcggc tcactgcaag ctccgcctcc caggttcaag tgactctcat 114060 

gcctcagcct ccctagtagc tgggattaca gactgagatt actgggtgcc accacaccca 114120 

gtaatttttt tatttttatt ttttctagta gagacagggt ttcaccatgt tggccaggct 114180 

ggtctcaaac tcctgacctc aagtaatccg cccaccttgg cctcccaaag tgcggggatt 114240 

acaggcttga gccactgcac ctggccttaa gtttcagtta aataatttaa aaagtttttc 114300 

ttattctttc cagaaaacct tttcattaat gtgttagctt tacttggtgg aacataagct 114360 

ttaaatcagt gcatctcaaa ctttccaaca acaaaaagta aactgacatt cccaggatgt 114420 

ctgagagtct ataacccaaa actattttag gttacttgcc attattgatt aagatagaaa 114480 

tttccagatg taccttacca tacagctctg tatcttatag ctttatatgt cccacatata 114540 

cgaacctgtt tcagattcat ggctttaaat tattgtctga ctcatttatc catgttctta 114600 

tatcagctcc tctttacaat taatgttgta cattttcagg gttggtggtt aatgggaggt 114660 

ccagaggaag tgatgtcagc aagatggctg actagaagcc cctagtgctt gctcccctca 114720 

caaagaaagc cagaaaaaca gataaacaac tacatttttt ttttttaacg gagtctcact 114780 

ctgtcaccca ggctggagta cagtagtgtg atcttggctc actgcaacct ctgtctccca 114840 

ggttcaagca attctcctgc ctcagcctcc caagtagctg ggactacagg cacccaccac 114900 

catgccgagc taatttttgc atttttagta gagatgggat ttcaccatga tggccaggct 114960 

ggtgtcgaac tcctgacctc aggcaatccg cccacctcag cctaccaaag tgctgggatt 115020 

acagacatga gccaccatgt ccgacctttt ttttttttga gatggagttt tgcttttgtc 115080 

gcccacgcta gagtgtaatg gcgtgatccc aggctagagt gtaatggcgt gatctcagct 115140 

cactgcaatc tccacctccc aggttcaagc gattcttctg cctcagcctc cggagtagct 115200 

ggaattatag gcttctgcca ccacacgcgg ctaattttta tatttttagt agagatgagg 115260 

tttcaccatg ttggccagga tggtcttgaa ctcctgacct ccggcgatcc acttgcctca 115320 

gcctctcaaa gtgctgggat tgtaggcatg aatcactgca ctgggccaaa caactatatt 115380 

ttaatgaaaa taactgaggg agagccctgg agtgcatcag aggagtaaca gaaaccctgg 115440 

tgagcacaga aactcgggat gaccacacag agaacagaaa gaaacactga gcctccacta 115500 

ctccatctcc aaatcaggat cagctgggaa ccaggaggaa cttctccctg cagtgaacag 115560 

ataagcaaga ggatcccagc aatccccatc aacaccttgg acacctacac tggggtcccc 115620 

agcactgttc ttaggcacta atcccatctt ggggagttgc ctggagtcca cataagtgta 115680 

ccctcccaac ccgagaaaag gagctgatac tgtgctccac ccactgtggt ccaagcagct 115740 

actgcactac tccatcttgg aagtggaact atagctggga tatgtcttgc tccaggggca 115800 

agtagccatg actcctcttt attgttaagg ctatgctatc accaaattac tccagcccag 115860 

tggcctgaca gccctgtcga gctgcaagca cctgttacac cttgtgcctt ggccatttaa 115920 

agagatcata cctcggccag gtgcggtggc tcacacctgt aatcccagca cttcgggagg 115980 

ccgaggcggg catatcacct gaggtcagga gtttgagaac agcctggcca acatggtgga 116040 

accctgtctc tactaaaact acaaaacaaa ttagttggac gtcatggcgc gcgcctgtag 116100 

tcccagctac tccagcctgg gcaacagagt gagactcagt ctctatttaa aaaaaaaaaa 116160 

aaaaaaaaaa aaaaaaaaaa gaggtcatac ctctccagtg cctaaattga aggagtacat 116220 

tgcatctcaa tgtactaagc agtgccttag tcatccagag cagtcacaca ctccagtacc 116280 

taagctgaag cagtgccctg catatcaggg aaaccatgtc tgggccaccc agaacaggca 116340 

tagccccatg cctgagctga actggcactg gggaattggt gccctggaag atctgagcag 116400 

ctctgtatcc catagatatt gggatagccc aaatatattg agatacaaga aaataccaat 116460 

agacaactca acaaaatcgg gaaagcaggc cggccgcagt ggctcacgcc tgtaatctca 116520 

ttactttggg aggccgaggc aggcagaaca cctgaggtcg ggagttcaag accagcctga 116580 

ccaacatgga gaaaacttgt ctgtattaaa aatacaaaat tagctggggt ggtggcacat 116640 

gcctataatc ccagctactc gagaggctga ggcaggagaa ttgcttgaac ctgggaggtg 116700 

gaggttgcag tgagccgaga tcacgccact gcactccggc ctgggcaaca agagcgaaac 116760 

tctgcctaaa aaaaagatcg ggaaagcaat tcacaatatg aacaagaaat tcaacaaaaa 116820 

gatagaaatt taaaaagaac caaacagaaa tcttcagctg aagaattcaa tggaaaatac 116880 

aaaatataat agagagcttc aacagcagat ttgatcaagc agaagaatct ctgaacttga 116940 

agacaggtca tttgaaaaaa aaatcggagt cagaaaaaaa aaagaagtaa gaatgaaaaa 117000 

gagtgaagag cgcctctgag acttatgaaa caccagtaag caaataaata tttgtattat 117060 

gggagttcca gaaggagaag agaaagggaa aggtgtagaa aaatctgctt aatgaaatat 117120 

taggttgggc atggtggctt acacctgtaa tcccaacact ttgggaggcc aaggtgggca 117180 

gaccgctttt gctcatgagt tttgagtcca gcctgggcaa catggtgata ccccatccct 117240 

acaaaaaata caaaaattag ccaggcatgg tggcatgcac ctgtagtccc agctactcgg 117300 

gactgaggca ggaggatcac ttgagccggg gaggttgagg ctgcaacgag ctgagatcac 117360 

accactacac tctagcctgg gatgacagag tgaggccctg tctcaaaaaa aaaagaaata 117420 

atagctgaaa acttcccaaa tctggggaga aatatagaca tctagatcta ggaggctcaa 117480 

aagtctccaa acagatcgaa ccctaaaagg ttcttcccaa ggaacattgt agtcaaattg 117540 

tcaagtcaag gacagacaga attctaaaaa caacagaaaa gcatcaagtc acttagaatc 117600 

ttcattaaac taacagcaga tttctccaca gaaaccttat aggcctggag agattgagat 117660 

gatatattca aagggctgaa aaaaaaaatt gtcagccaag aatgctgtac ccagtagagg 117720 

atcatgtgag ctcaggaggc agaggttgca gtgagctatg attgtgccac tgtactccag 117780 

cctgggcaac ggagtgagac cctgtctcaa tcattcaatc aatcaatcaa tcaatcaata 117840 

agaatcctat ttccagcaaa gctaactttt agaaatgagg gagaaatagt atttccgaga 117900 

catgcataaa ctgaggacat ttatcaccac tagattcgac ctataggaaa tgttcgaggg 117960 

aggcaaaaag tcaataatca ttattatgga aacaacagta taaaactcac tggtagaaca 118020 

gatacacaag aaagaaacag aaaagattca aaccttgttg ctctacagaa aaccaccaac 118080 

ccaccatgat aataagaaga aaggaagaaa ggatatagaa aacaagcaga aaacaattaa 118140 

caaaatgaca ggaataggcc ttcacctatc agtagtaact ctgaaggtaa acaaattaaa 118200 

ttgcccactg aaaagatgta gactggctaa atgaattttt ttctcactct ggtttccagg 118260 

ctggagtaca gtggtgcaat ctcaactcac tgcaacctct gcctcctggg ctcaggcgat 118320 

cctcttgccc cagcctcctg catggctggg actacaggca tgcatcacca cacaaggcat 118380 

gcatcaccac acctggctta tttttgtatt tttgtagaga cgggatatca ctatgttgcc 118440 

cagactggtc ttgaatccag agctcaagca atccacctgc ctcatccttc caaagtgctg 118500 

ggattactgg cgtgagccac caagcccagc cactgaatga attttttaaa agaatgaaac 118560 

catatccttt acagcaacat agatggagct gaaggtcata atcctaagca aactaacaca 118620 

ggaacagaaa accaaatact gcatgctctc acttaaaagt gggagctaaa cattgagcac 118680 

acatggacat aacatgggaa taataaacac tgtggactac tagagaggag ggcagggggg 118740 

atgggttgaa aaattctatt ggggctgggt gcagtggctc acgcctgtaa tcccagcact 118800 

ttgggaggcc aaggccggtg aatcacaagg tcaagagatc aagactgtct tggccaacat 118860 

ggtgaaaccc catctctact aaaaatacaa aaattagcca ggcatggtgg cacgcacctg 118920 

tagtaccagc tacttgggag gctgaggcag gaggatcact tgaactcagg aggcagaggt 118980 

tgtagtgagc cgagattgcg ccactgcact ccaacctggc gacagagcaa ggctctatct 119040 

caaaaaaaaa aaaaagaaaa gaaaaactac tgggtgctaa gctcaccatc tgggtgtaat 119100 

atacccatgt aacaaatctc acatgtacct cctatattta aaatactgaa ttttttaaca 119160 

atccaaatat atgctgccta tgagaaattc acttcacctg taaagacaca tataaactga 119220 

aagtgaagag atggagaaag tcattcattc catgcaagcg gaaaagaaat gcaagcagga 119280 

gtagctgtat ttaagttaga caaaacagac tttaagtcaa aaactataaa atgagacaaa 119340 

gaaggtcatt atataatgct aaagggatca atttaccaag aggatataac agttgtaaat 119400 

atatatgcag ccaacactgg agcatccaga tatataatat aaagcaagta ttattagctc 119460 

taaagaaaga aggagactcc aataatagta gttgagaact tcaacacccc actgtcagcg 119520 

cttgacagat catctagaca gaaaatcaac aaagaaacat tggatttaaa atacacttta 119580 

gaccaaatgg acctaacaaa tatatacaaa gcatttcatc cagcagctgc agaatataca 119640 

ttattttctc agcacatgga acattcacca ggatagacca catgttaggc cacaaaacaa 119700 

atttcaacaa atttaaaata atggaggcgg tcaggtgtgg tggctcatgc ctataatccc 119760 

agtactttgg gaggccaagg tgagtggatc acttgaggtc aggagttcaa gaccaccctg 119820 

gccaacatga tgaaacccca cctctactaa aaatacaaaa attagccagg agtggtggca 119880 

catgcctgta atcccagcta ctcaggaggc tgaggcaaga gaatcgcttg aacctagaag 119940 

gtggaggttg cagtaaacca agatcacgcc actgcactcc agcctgggcg acagagtgag 120000 

actgtctcaa aataaataaa ttaaattaaa taattgccgg gtgtggtagc tcacgcctgt 120060 

aatcccagca ctttgggagg ctgaggcagg tggatcactt gaggtcagga gttcgtgacc 120120 

agcctggcca acatggcaaa accccgtctc tactaaaaat acaaaaatta gccgggtgtg 120180 

gtggcgggcg cctataatcc cagctactca agaggctgag gcaggagaat cgcttgaacc 120240 

caggaggcag agattgcaga gccgagatca caccattgca cactccagcc tgggtgactg 120300 

agtgggactc tatctcaaaa aaaaaaaaaa aaaaagatac ttgatttgat ttctttcgtt 120360 

ttgttttgtt ttgttttgtt ttgttttgtt tgagacaggg tctcactctg gtgagatcat 120420 

ggctcacagg aaccttcgcc tcctgggctc aagtgatcct cccacatcag cctcccgagt 120480 

agctagggcc acagacacat gccaccatgc ctggctaatt ttgacatttt ttgtagagac 120540 

aaggtttttc actatgttac ccaggctgag tttaagcagt ccacctacct tggcctccca 120600 

aagtgctggg attacagatg ttagccactg cacccagcct caattatttt tttgatttaa 120660 

tgttggccag gctggtctcg aactcctgac ctcaaatgat ccgcctgcct cggcctccca 120720 

aagtactagg attacagtca tgagttacca tgcccggcct caaatatctt ttacatggaa 120780 

attaaacagt atgctcctga acaaccagtg actggtcaat gaagaaatta agaagaaatt 120840 

tttaaaattt cttggaacaa atgaaaatag aaatacaaca ttccaaaccc tgtgggatag 120900 

agcaaaaaca gaattcagag ggaagtttat agcaataaac atttacatca aaaacataga 120960 

aacggctggg cacatggtac atgcctgtaa tcccagcttc tcaggaggct gaggcaggag 121020 

gactgcttga gcccacaagt tcaagacaag cctgggcaac atagtgagac ctcatctcta 121080 

caaaaaataa aaaaattagc tggacgtgct gacatgtacc tgtggtccca gctactcagg 121140 

aggcagaggt gggaggatca ctggagccca gaagggcaag gctgcaatga gcctgggcaa 121200 

cagaacaaga ctctgtctca aaaaaacaag gtattaatat ccaggatatc caaagaactc 121260 

aaacaactca acagcaaaaa taataataat aatttgattt taaaataggc aaatgtctca 121320 

agagagtaat tgagacgatc aagaggtata tgaaaaaatg ctcaacatca ataatcacca 121380 

ggggaatgcc aattaaaatc acaatgagat atcatctcac tcaaattaat atagtcatta 121440 

tcaaaaagac aaagaatgca gagaaagggg aactcatatg cactattggt ggcaatgtac 121500 

attagtacag ccattaggga aatcagtatg gaagttcctc ataaaactga aattaaaact 121560 

accatatgat ccagccatcc cactactgag tatatatgca aaggaaagga aacagtgtgt 121620 

caagaagata tctgcatccc catgtttatt gcagtactat tacaataggc aagatatgga 121680 

atcaacctaa gtgtccctca acagatgaat gaagaaaata tggtatttat acacaatgaa 121740 

atactattta gccacaaaaa aagaatgaaa ttctgtcatt tgtggcaaca tggatgagtc 121800 

tggaggacat tatgttacat gaaataaacc aaccacagag agatatatac tgcatgatct 121860 

cactggtgga agctataaaa gttgatgtca tagaagtaga gagtaaaata gtagttacta 121920 

gaggcaggaa agggaggggg attaccaaag actggttaac agatacaaaa ttacaactag 121980 

ataggaggaa taagttctaa tattctatag cactatagga tggctgtaat taccaactta 122040 

ttgtatattt tcaaataacc aggagagtgg gtttggaatt ttcctggcac aatgtttgag 122100 

gcatagatat cctaattacc ctgatttgat cattatacat tatatatgtg tatcaaaata 122160 

ttacactgta cctcataaat atgtgtaatt attatgtgtc catgaaaaat aacaaaagcc 122220 

aaaaaaagtt aatagtatct tctagggatt aaaacctata tatatcaggc tcaggcctgt 122280 

aatctcagca ctttgggagg ccgaggcgag tggattgctt cagcccaaga gttggagacc 122340 

agtctgggca acatggcaaa acctcatctc tataaaaaat aaaaaaatta gctgggtgtg 122400 

gtggtaggtg cctgtagtcc cagctactcc ggaggctgag gggaggatca cctgagcctg 122460 

ggaggtcgag actgcagacc ctgtctctaa ataaataaat aaataaatcc tatatgactg 122520 

gtttatatat tttaacctag tgtttcctcc agtatttaat aaataccaca ttgcatccag 122580 

atgactgtat tttaaaaatc acagaggaga aagattctct cttcaagtta agttttagaa 122640 

atgctgttaa acagattttt tttattacgg aacttttgaa gaccattgat atgcaaatga 122700 

ccattatgaa tcttcaagat agaaatattt ctccgatata tttaatcaga aaccttaggg 122760 

aacagttttc cttttttttt ttaactttta aaatttttat ttttatttat ttatttactt 122820 

tttgagatgg agtctcgctc tgtcacccag gctggagtgc actggtgcag tcacggctta 122880 

ctgcaacctc cacctcccag gttaaagaga ttctcctgcc tcaccctccc aagtagctgg 122940 

actacaggca catgccacta cacccagctc attttttgta tttgtagtag agagggggtt 123000 

ttgccatgtt gggcaggctg gtctcgaact cttgttcgat ccacctacct tgtcctccca 123060 

aagtgctggg attacaggtg tgagccacca cacccagcct atttttgttt tattatttat 123120 

ttgagacagg gtcttgctgt gttgcccagg ctggagtgca gtggcacaat caccactcac 123180 

tgcagccttg acttcctgag ctcagcaatc ttcctgcctc agcctcccac ctagctggga 123240 

ctacaggtcc acaccaccac acctggctaa tttttttttt tttttttttt ttttgagaca 123300 

gtctcgctct gtcaccaggc tgaagtgcag tggtgcgatc tcggctcact gcaacctcca 123360 

actccctggt tcaagcgatt ctcctgcctc agcctcctga gtagctgggc ttacaggcac 123420 

gcatcaccac gcctagctaa tttttgtatt tttagtagag atggggtttc accatattag 123480 

ccaggatggt cttgatctcc accacatctg gcccacacct ggctaatttt ttaaatcttt 123540 

ttgtagagat gaggtcttcc tatgttgcct aggctagtca caaactcctg ggcttgagct 123600 

gtcctcccac ctcagcctcc ccaaagtgct gagactataa gcatgagcca ccatgcccag 123660 

cctgaacaga tttcctttag gatatcagtt tgaaacttct gctgtagtca gcaaataacc 123720 

aataatattt cacagagact aaaaactgtt ctttatacat cttcccagct ttacttttct 123780 

attttatttt atttcatttc atttatttat ttattgagac aaagtttcac tatgtcaccc 123840 

aggctggagt gcaatgatgg gatcatagtt cactgcagcc ttgacctcct gggctcaagt 123900 

gatctgcctg cctcagcctc ccaagtagct gggactacag gtgcatgcca ccacatctgg 123960 

ctaatttttt ttttaccttt tgtggagatg gagcctcact gtgttgtgca ggctggtctt 124020 

gaactcctgg cctcaagcta ccctcccact ttaacctccc aaagtgccaa acctgttttt 124080 

tatgtgactt ggtattaaat atttattaaa aagttcaaaa ttgggctcag cacagtagct 124140 

cacgcctgta attccagcac tttgggaggc tgaggcaggc agatcgttta aggtcaggag 124200 

tttgagacca gcctgaccaa catggcaaaa ccctgtccct actaaaaata caaaaaatta 124260 

gctgggcatg atcacacatg cctgtaatcc cagctactgg ggaggcagag gcactagaat 124320 

cttttgagcc ccagaggtgg aggttgcagt gatctgagat cacgccattg cacttcagcc 124380 

tgggtgacag agcaagactt tgtctcaaaa aacaaaacaa aacaaaaaga gttcaaaatt 124440 

caacagtgta tgtcattgcc ttctctatag ggtaccagtc gtccttcaca ctatcatgtt 124500 

ttatgggatg ataactgctt tactgcagat gaacttcagc tgctaactta ccagctctgc 124560 

cacacttacg tacgctgtac acgatctgtt tctatacctg caccagcgta ttatgctcac 124620 

ctggtagcat ttagagccag atatcatctt gtggacaaag aacatgacag gtaatataaa 124680 

agcataacag gttctcaccc aaatcccaat attgtctgca tggtaggatt ttcaagttcc 124740 

acaagctatt agcggagtca gtgatccatg tgaaaaatga tgacagaact gactgcccaa 124800 

ggtttcctat tgaaatatat tgtctaggct cattagtaat agaatcatgt agtaacttag 124860 

ttgttttact acattaattc aaaggagaga ttattggtaa taaagtgata cattcagaca 124920 

gatagacaaa atgatacgat atctaggttt gcttctaatt aattctgggg aggtgagaga 124980 

agtaaaacaa aattggcctt gagttaatag tgattgaagc tgagtgatgg acacatagat 125040 

tgttacacca gtctcttatt tgttaataat tttgaaattt tctacaacaa atagtatttt 125100 

tcggaattat tacatcagaa tagaaagttt gtttttgtgt tcattgccac ttctcttaca 125160 

gtgctgaagg aagtcacgtt tcaggacaaa gcaatgggcg agatccacaa gctcttgcca 125220 

aggctgtaca gattcaccaa gataccttac gcacaatgta cttcgcttaa atagtccaag 125280 

tatattctct gagaggaagt actgaaagat gaattgacat acaacgtatg tttccagtga 125340 

agtcaattga gtaaggacac ctccagccat acagaaacca acactgtgtg ggggccaagg 125400 

tctgatcctt atgttaatac aaggaagatt gtttacttca tcaaggaaca cagcatcatt 125460 

atgcaatatg aaaccagcca actgcttttt gtgcggtctc ctataggaag tatcgcaatt 125520 

gttttgtttt catttcttgt agtctaaccc ttttaatgcc tttacctcaa gttgcttggc 125580 

agcacaacta tctttgcaaa aaaaagtaaa gaaaaagtaa atgatggttt aaaaaataca 125640 

caccttcatg aataatcaaa gtgatttttc agaattatgt gtgcaaaaaa ttaatgtgca 125700 

ttcatatatt cttgtaaaag gtgtctgtgt atttttaaaa tatatacatc catacttcat 125760 

atgcatatat atctagatct ggattgataa tagatatata tgtgtctgtt atatatttta 125820 

gagttcattc cattggggaa ttttctttcc cttttattct acccccacta ccgcctttat 125880 

ttctctattt cccttgcctt catcacctac atttttttcc cagtcctacc agtgacattc 125940 

aaatgttgat gtatctggtt cgtttgaata taaaatatgg caaactagaa ttctactttt 126000 

a                                                                 126001 

 
           
             14  
             1726  
             DNA  
             H. sapiens  
             
 
             
               CDS  
               (280)...(969)  
             
           
            14 

aggaaggagg gtggccctac cccagcgggc tcggctcggg gcctccgcgg cagttcgggg     60 

tccttcaccc gccggctcca gtcctgtgcc gttttccgtc cgcgactctt ccggcccaga    120 

gctttcggag tgcggttgct caggggaagc cgtcgccgcc cccgcctcgg ggccgagtga    180 

gagtgcccgt cgcgtcgcgc cgcgtcgccc cccgggccgc ctccttgccg ccagtggcgg    240 

gctccgttct ccctcgaagc actcccccca gctccatga atg gaa atc ggc tcc       294 
                                           Met Glu Ile Gly Ser 
                                             1               5 

gca gga ccc gct ggg gcc cag ccc cta ctc atg gtg ccc aga aga cct      342 
Ala Gly Pro Ala Gly Ala Gln Pro Leu Leu Met Val Pro Arg Arg Pro 
                 10                  15                  20 

ggc tat ggc acc atg ggc aaa ccc att aaa ctg ctg gct aac tgt ttt      390 
Gly Tyr Gly Thr Met Gly Lys Pro Ile Lys Leu Leu Ala Asn Cys Phe 
             25                  30                  35 

caa gtt gaa atc cca aag att gat gtc tac ctc tat gag gta gat att      438 
Gln Val Glu Ile Pro Lys Ile Asp Val Tyr Leu Tyr Glu Val Asp Ile 
         40                  45                  50 

aaa cca gac aag tgt cct agg aga gtg aac agg gag gtg gtt gac tca      486 
Lys Pro Asp Lys Cys Pro Arg Arg Val Asn Arg Glu Val Val Asp Ser 
     55                  60                  65 

atg gtt cag cat ttt aaa gta act ata ttt gga gac cgt aga cca gtt      534 
Met Val Gln His Phe Lys Val Thr Ile Phe Gly Asp Arg Arg Pro Val 
 70                  75                  80                  85 

tat gat gga aaa aga agt ctt tac acc gcc aat cca ctt cct gtg gca      582 
Tyr Asp Gly Lys Arg Ser Leu Tyr Thr Ala Asn Pro Leu Pro Val Ala 
                 90                  95                 100 

act aca ggg gta gat tta gac gtt act tta cct ggg gaa ggt gga aaa      630 
Thr Thr Gly Val Asp Leu Asp Val Thr Leu Pro Gly Glu Gly Gly Lys 
            105                 110                 115 

gat cga cct ttc aag gtg tca atc aaa ttt gtc tct cgg gtg agt tgg      678 
Asp Arg Pro Phe Lys Val Ser Ile Lys Phe Val Ser Arg Val Ser Trp 
        120                 125                 130 

cac cta ctg cat gaa gta ctg aca gga cgg acc ttg cct gag cca ctg      726 
His Leu Leu His Glu Val Leu Thr Gly Arg Thr Leu Pro Glu Pro Leu 
    135                 140                 145 

gaa tta gac aag cca atc agc act aac cct gcc cat gcc gtt gat gtg      774 
Glu Leu Asp Lys Pro Ile Ser Thr Asn Pro Ala His Ala Val Asp Val 
150                 155                 160                 165 

gtg cta cga cat ctg ccc tcc atg aaa tac aca cct gtg ggg cgt tca      822 
Val Leu Arg His Leu Pro Ser Met Lys Tyr Thr Pro Val Gly Arg Ser 
                170                 175                 180 

ttt ttc tcc gct cca gaa gga tat gac cac cct ctg gga ggg ggc agg      870 
Phe Phe Ser Ala Pro Glu Gly Tyr Asp His Pro Leu Gly Gly Gly Arg 
            185                 190                 195 

gaa gtg tgg ttt gga ttc cat cag tct gtt cgg cct gcc atg tgg aaa      918 
Glu Val Trp Phe Gly Phe His Gln Ser Val Arg Pro Ala Met Trp Lys 
        200                 205                 210 

atg atg ctt aat atc gat gaa aga gac ctc tgg cag cag tgt gga gaa      966 
Met Met Leu Asn Ile Asp Glu Arg Asp Leu Trp Gln Gln Cys Gly Glu 
    215                 220                 225 

tag atagaggaga aaaaactaat ctgagaagcc agttaggagg cttttcaatc          1019 

actagttcag gtaagagatg gtgatggtct aatgtgggat ggagaggaag gattaagctg   1079 

aaaaaatagg tttaagaacc atgtccagaa aaaaaaaact ttgggtgtag tactggtaca   1139 

tggaacggat tggaaaaaaa tagaccagag ctttactaga tttttgaaag aattgttttt   1199 

gcaaataaac tacaagcctg gcatatcagt caaggttcag aacctagaga agcagaacca   1259 

gtacgaagta tagagagaga gtttatgcaa ttgtaggggc tagctaggca agtctgaaat   1319 

tttgggggca ggctgtcagg aagggcaggg aaattcaggc atgggctgaa gcagttatct   1379 

ataagtggaa tttcttgctc tcagggaagc ttcagcccta cttttaagac ctttcaccta   1439 

attgaatcag gcccatccac attattcagg ataatctcca ttacttaaag tcaacagatt   1499 

atggatttta atcacatcta caaaatacct tcatagcaac acctagatta gtgtttgatt   1559 

aaacaaatgg cagctggtag cctagcaagt taacacatta aaaacaacac ctgccatgat   1619 

ggcttacact tgtaatccca gcactttggg aggccaaagt gggaggatca cttgagatta   1679 

ggagtttgcg atcaggctga acaacatagt gagacctgat ctctacc                 1726 

 
           
             15  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            15 

agaacggagc ccgccactgg                                                 20 

 
           
             16  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            16 

ccgatttcca ttcatggagc                                                 20 

 
           
             17  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            17 

cttgaaaaca gttagccagc                                                 20 

 
           
             18  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            18 

tcatagaggt agacatcaat                                                 20 

 
           
             19  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            19 

gtcaaccacc tccctgttca                                                 20 

 
           
             20  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            20 

attgagtcaa ccacctccct                                                 20 

 
           
             21  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            21 

ctttaaaatg ctgaaccatt                                                 20 

 
           
             22  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            22 

ccatcataaa ctggtctacg                                                 20 

 
           
             23  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            23 

tggcggtgta aagacttctt                                                 20 

 
           
             24  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            24 

agtggattgg cggtgtaaag                                                 20 

 
           
             25  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            25 

ctgtagttgc cacaggaagt                                                 20 

 
           
             26  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            26 

ctaaatctac ccctgtagtt                                                 20 

 
           
             27  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            27 

gtcctgtcag tacttcatgc                                                 20 

 
           
             28  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            28 

ctaattccag tggctcaggc                                                 20 

 
           
             29  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            29 

catcaacggc atggacaggg                                                 20 

 
           
             30  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            30 

tttcatggag ggcagatgtc                                                 20 

 
           
             31  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            31 

aggtgtgtat ttcatggagg                                                 20 

 
           
             32  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            32 

tctggagcgg agaaaaatga                                                 20 

 
           
             33  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            33 

gaacagactg atggaatcca                                                 20 

 
           
             34  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            34 

ctcattgttc cacaatgagt                                                 20 

 
           
             35  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            35 

gcctccttgt tacattacaa                                                 20 

 
           
             36  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            36 

tctctccaca gtttggccgt                                                 20 

 
           
             37  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            37 

agagtatact tttctctgaa                                                 20 

 
           
             38  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            38 

gggtacttca gctgaagagt                                                 20 

 
           
             39  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            39 

cctgcccgac ttgcagacag                                                 20 

 
           
             40  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            40 

tcttgtctat ctggtgcaga                                                 20 

 
           
             41  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            41 

aatttgcact tcttaccaat                                                 20 

 
           
             42  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            42 

gatctgtttc ataatttgca                                                 20 

 
           
             43  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            43 

tgaaactcct gaacaaatgg                                                 20 

 
           
             44  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            44 

ctttaaattg aaactcctga                                                 20 

 
           
             45  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            45 

atcccgaact ttaaattgaa                                                 20 

 
           
             46  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            46 

ccatttcatc ccgaacttta                                                 20 

 
           
             47  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            47 

acatgagcca tttcatcccg                                                 20 

 
           
             48  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            48 

gaagtacgcg tccagttaca                                                 20 

 
           
             49  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            49 

ctgtccgatt ccgtcctcca                                                 20 

 
           
             50  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            50 

catactccat ggctcggtgt                                                 20 

 
           
             51  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            51 

ttcaactcct gtgtggaatt                                                 20 

 
           
             52  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            52 

gtgaaaccct tcaatatttc                                                 20 

 
           
             53  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            53 

gccagaatat gtgttcttga                                                 20 

 
           
             54  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            54 

gacgataata agctgtaggc                                                 20 

 
           
             55  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            55 

ttacattctt gacttgaaca                                                 20 

 
           
             56  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            56 

taacatttat ctttaggcac                                                 20 

 
           
             57  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            57 

aatattattg atccctccga                                                 20 

 
           
             58  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            58 

gtggatgagt gacatcggct                                                 20 

 
           
             59  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            59 

aagttcccgg accatggagg                                                 20 

 
           
             60  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            60 

cctctgaaac accatcccga                                                 20 

 
           
             61  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            61 

tagttcataa tataatacct                                                 20 

 
           
             62  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            62 

ctccaaactg atgcaggctt                                                 20 

 
           
             63  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            63 

tacaatgtag gttattccag                                                 20 

 
           
             64  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            64 

gcacaaaata atcgagtgtg                                                 20 

 
           
             65  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            65 

tccaaccctt tctgtcctat                                                 20 

 
           
             66  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            66 

gggatattgc cacttcttcc                                                 20 

 
           
             67  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            67 

gtgtgtaatg tctgtatcaa                                                 20 

 
           
             68  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            68 

ctaccaggtg agcataatac                                                 20 

 
           
             69  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            69 

ccttggcaag agcttgtgga                                                 20 

 
           
             70  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            70 

ttgtgcgtaa ggtatcttgg                                                 20 

 
           
             71  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            71 

ttggactatt taagcgaagt                                                 20 

 
           
             72  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            72 

agtacttcct ctcagagaat                                                 20 

 
           
             73  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            73 

ggaggtgtcc ttactcaatt                                                 20 

 
           
             74  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            74 

taaggatcag accttggccc                                                 20 

 
           
             75  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            75 

gatgctgtgt tccttgatga                                                 20 

 
           
             76  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            76 

agaccgcaca aaaagcagtt                                                 20 

 
           
             77  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            77 

caaagatagt tgtgctgcca                                                 20 

 
           
             78  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            78 

aggtctcttt catcgatatt                                                 20 

 
           
             79  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            79 

gctttcgttc taacaggagg                                                 20 

 
           
             80  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            80 

tggtgaataa aatgacaatc                                                 20 

 
           
             81  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            81 

cagaaatcca ccacccaata                                                 20 

 
           
             82  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            82 

ataccacgtt ctgatttccc                                                 20 

 
           
             83  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            83 

aaccacctcc ctaaagaagg                                                 20 

 
           
             84  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            84 

aggtctcttt ctggaaaaca                                                 20 

 
           
             85  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            85 

aagcatagaa actttcagtt                                                 20 

 
           
             86  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            86 

gagactttac ccgtcctcca                                                 20 

 
           
             87  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            87 

accagtcaga ctctctgtgt                                                 20 

 
           
             88  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            88 

gaactcctga cctcaggtga                                                 20 

 
           
             89  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            89 

gtaggcttac ctgtattcca                                                 20 

 
           
             90  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            90 

cggcacagga ctggagccgg                                                 20 

 
           
             91  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            91 

tgagcaaccg cactccgaaa                                                 20 

 
           
             92  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            92 

ttcccctgag caaccgcact                                                 20 

 
           
             93  
             20  
             DNA  
             H. sapiens  
             
 
           
            93 

ccagtggcgg gctccgttct                                                 20 

 
           
             94  
             20  
             DNA  
             H. sapiens  
             
 
           
            94 

gctccatgaa tggaaatcgg                                                 20 

 
           
             95  
             20  
             DNA  
             H. sapiens  
             
 
           
            95 

gctggctaac tgttttcaag                                                 20 

 
           
             96  
             20  
             DNA  
             H. sapiens  
             
 
           
            96 

attgatgtct acctctatga                                                 20 

 
           
             97  
             20  
             DNA  
             H. sapiens  
             
 
           
            97 

tgaacaggga ggtggttgac                                                 20 

 
           
             98  
             20  
             DNA  
             H. sapiens  
             
 
           
            98 

agggaggtgg ttgactcaat                                                 20 

 
           
             99  
             20  
             DNA  
             H. sapiens  
             
 
           
            99 

aatggttcag cattttaaag                                                 20 

 
           
             100  
             20  
             DNA  
             H. sapiens  
             
 
           
            100 

cgtagaccag tttatgatgg                                                 20 

 
           
             101  
             20  
             DNA  
             H. sapiens  
             
 
           
            101 

aagaagtctt tacaccgcca                                                 20 

 
           
             102  
             20  
             DNA  
             H. sapiens  
             
 
           
            102 

ctttacaccg ccaatccact                                                 20 

 
           
             103  
             20  
             DNA  
             H. sapiens  
             
 
           
            103 

acttcctgtg gcaactacag                                                 20 

 
           
             104  
             20  
             DNA  
             H. sapiens  
             
 
           
            104 

aactacaggg gtagatttag                                                 20 

 
           
             105  
             20  
             DNA  
             H. sapiens  
             
 
           
            105 

gcatgaagta ctgacaggac                                                 20 

 
           
             106  
             20  
             DNA  
             H. sapiens  
             
 
           
            106 

gcctgagcca ctggaattag                                                 20 

 
           
             107  
             20  
             DNA  
             H. sapiens  
             
 
           
            107 

ccctgtccat gccgttgatg                                                 20 

 
           
             108  
             20  
             DNA  
             H. sapiens  
             
 
           
            108 

gacatctgcc ctccatgaaa                                                 20 

 
           
             109  
             20  
             DNA  
             H. sapiens  
             
 
           
            109 

cctccatgaa atacacacct                                                 20 

 
           
             110  
             20  
             DNA  
             H. sapiens  
             
 
           
            110 

tcatttttct ccgctccaga                                                 20 

 
           
             111  
             20  
             DNA  
             H. sapiens  
             
 
           
            111 

tggattccat cagtctgttc                                                 20 

 
           
             112  
             20  
             DNA  
             H. sapiens  
             
 
           
            112 

actcattgtg gaacaatgag                                                 20 

 
           
             113  
             20  
             DNA  
             H. sapiens  
             
 
           
            113 

ttgtaatgta acaaggaggc                                                 20 

 
           
             114  
             20  
             DNA  
             H. sapiens  
             
 
           
            114 

acggccaaac tgtggagaga                                                 20 

 
           
             115  
             20  
             DNA  
             H. sapiens  
             
 
           
            115 

ttcagagaaa agtatactct                                                 20 

 
           
             116  
             20  
             DNA  
             H. sapiens  
             
 
           
            116 

actcttcagc tgaagtaccc                                                 20 

 
           
             117  
             20  
             DNA  
             H. sapiens  
             
 
           
            117 

ctgtctgcaa gtcgggcagg                                                 20 

 
           
             118  
             20  
             DNA  
             H. sapiens  
             
 
           
            118 

tctgcaccag atagacaaga                                                 20 

 
           
             119  
             20  
             DNA  
             H. sapiens  
             
 
           
            119 

attggtaaga agtgcaaatt                                                 20 

 
           
             120  
             20  
             DNA  
             H. sapiens  
             
 
           
            120 

tgcaaattat gaaacagatc                                                 20 

 
           
             121  
             20  
             DNA  
             H. sapiens  
             
 
           
            121 

ccatttgttc aggagtttca                                                 20 

 
           
             122  
             20  
             DNA  
             H. sapiens  
             
 
           
            122 

tcaggagttt caatttaaag                                                 20 

 
           
             123  
             20  
             DNA  
             H. sapiens  
             
 
           
            123 

ttcaatttaa agttcgggat                                                 20 

 
           
             124  
             20  
             DNA  
             H. sapiens  
             
 
           
            124 

taaagttcgg gatgaaatgg                                                 20 

 
           
             125  
             20  
             DNA  
             H. sapiens  
             
 
           
            125 

cgggatgaaa tggctcatgt                                                 20 

 
           
             126  
             20  
             DNA  
             H. sapiens  
             
 
           
            126 

tgtaactgga cgcgtacttc                                                 20 

 
           
             127  
             20  
             DNA  
             H. sapiens  
             
 
           
            127 

tggaggacgg aatcggacag                                                 20 

 
           
             128  
             20  
             DNA  
             H. sapiens  
             
 
           
            128 

acaccgagcc atggagtatg                                                 20 

 
           
             129  
             20  
             DNA  
             H. sapiens  
             
 
           
            129 

aattccacac aggagttgaa                                                 20 

 
           
             130  
             20  
             DNA  
             H. sapiens  
             
 
           
            130 

gaaatattga agggtttcac                                                 20 

 
           
             131  
             20  
             DNA  
             H. sapiens  
             
 
           
            131 

tcaagaacac atattctggc                                                 20 

 
           
             132  
             20  
             DNA  
             H. sapiens  
             
 
           
            132 

gcctacagct tattatcgtc                                                 20 

 
           
             133  
             20  
             DNA  
             H. sapiens  
             
 
           
            133 

tgttcaagtc aagaatgtaa                                                 20 

 
           
             134  
             20  
             DNA  
             H. sapiens  
             
 
           
            134 

gtgcctaaag ataaatgtta                                                 20 

 
           
             135  
             20  
             DNA  
             H. sapiens  
             
 
           
            135 

agccgatgtc actcatccac                                                 20 

 
           
             136  
             20  
             DNA  
             H. sapiens  
             
 
           
            136 

cctccatggt ccgggaactt                                                 20 

 
           
             137  
             20  
             DNA  
             H. sapiens  
             
 
           
            137 

tcgggatggt gtttcagagg                                                 20 

 
           
             138  
             20  
             DNA  
             H. sapiens  
             
 
           
            138 

aggtattata ttatgaacta                                                 20 

 
           
             139  
             20  
             DNA  
             H. sapiens  
             
 
           
            139 

aagcctgcat cagtttggag                                                 20 

 
           
             140  
             20  
             DNA  
             H. sapiens  
             
 
           
            140 

ctggaataac ctacattgta                                                 20 

 
           
             141  
             20  
             DNA  
             H. sapiens  
             
 
           
            141 

cacactcgat tattttgtgc                                                 20 

 
           
             142  
             20  
             DNA  
             H. sapiens  
             
 
           
            142 

ataggacaga aagggttgga                                                 20 

 
           
             143  
             20  
             DNA  
             H. sapiens  
             
 
           
            143 

ttgatacaga cattacacac                                                 20 

 
           
             144  
             20  
             DNA  
             H. sapiens  
             
 
           
            144 

gtattatgct cacctggtag                                                 20 

 
           
             145  
             20  
             DNA  
             H. sapiens  
             
 
           
            145 

tccacaagct cttgccaagg                                                 20 

 
           
             146  
             20  
             DNA  
             H. sapiens  
             
 
           
            146 

ccaagatacc ttacgcacaa                                                 20 

 
           
             147  
             20  
             DNA  
             H. sapiens  
             
 
           
            147 

acttcgctta aatagtccaa                                                 20 

 
           
             148  
             20  
             DNA  
             H. sapiens  
             
 
           
            148 

attctctgag aggaagtact                                                 20 

 
           
             149  
             20  
             DNA  
             H. sapiens  
             
 
           
            149 

aattgagtaa ggacacctcc                                                 20 

 
           
             150  
             20  
             DNA  
             H. sapiens  
             
 
           
            150 

gggccaaggt ctgatcctta                                                 20 

 
           
             151  
             20  
             DNA  
             H. sapiens  
             
 
           
            151 

tcatcaagga acacagcatc                                                 20 

 
           
             152  
             20  
             DNA  
             H. sapiens  
             
 
           
            152 

aactgctttt tgtgcggtct                                                 20 

 
           
             153  
             20  
             DNA  
             H. sapiens  
             
 
           
            153 

tggcagcaca actatctttg                                                 20 

 
           
             154  
             20  
             DNA  
             H. sapiens  
             
 
           
            154 

cctcctgtta gaacgaaagc                                                 20 

 
           
             155  
             20  
             DNA  
             H. sapiens  
             
 
           
            155 

gattgtcatt ttattcacca                                                 20 

 
           
             156  
             20  
             DNA  
             H. sapiens  
             
 
           
            156 

tattgggtgg tggatttctg                                                 20 

 
           
             157  
             20  
             DNA  
             H. sapiens  
             
 
           
            157 

gggaaatcag aacgtggtat                                                 20 

 
           
             158  
             20  
             DNA  
             H. sapiens  
             
 
           
            158 

ccttctttag ggaggtggtt                                                 20 

 
           
             159  
             20  
             DNA  
             H. sapiens  
             
 
           
            159 

tgttttccag aaagagacct                                                 20 

 
           
             160  
             20  
             DNA  
             H. sapiens  
             
 
           
            160 

tggaggacgg gtaaagtctc                                                 20 

 
           
             161  
             20  
             DNA  
             H. sapiens  
             
 
           
            161 

acacagagag tctgactggt                                                 20 

 
           
             162  
             20  
             DNA  
             H. sapiens  
             
 
           
            162 

tcacctgagg tcaggagttc                                                 20 

 
           
             163  
             20  
             DNA  
             H. sapiens  
             
 
           
            163 

tttcggagtg cggttgctca                                                 20 

 
           
             164  
             20  
             DNA  
             H. sapiens  
             
 
           
            164 

agtgcggttg ctcaggggaa                                                 20