Patent Publication Number: US-2003232771-A1

Title: Antisense modulation of MARK3 expression

Description:
FIELD OF THE INVENTION  
       [0001] The present invention provides compositions and methods for modulating the expression of MARK3. In particular, this invention relates to compounds, particularly oligonucleotides, specifically hybridizable with nucleic acids encoding MARK3. Such compounds have been shown to modulate the expression of MARK3.  
       BACKGROUND OF THE INVENTION  
       [0002] Microtubules are intracellular cytoskeletal components that participate in a variety of cellular processes, such as regulating cell shape, motility, and polarity, serving as tracks for cellular transport, and coordinating the dynamic chromosome movements of mitosis. Central to microtubule function is the property of dynamic instability. Microtubules transition between stable and dynamic states, and these transitions are modulated, in part, by structural microtubule-associated proteins (MAPs). Structural MAPs are filamentous proteins that lack enzymatic activity but bind reversibly to microtubules and stabilize them by promoting tubulin polymerization. The phosphorylation of MAPs influences their microtubule-stabilizing capacity. In mitotic cells, where the microtubule turnover rate increases 18-fold, MAPs exhibit a several-fold higher degree of phosphorylation. Microtubule-affinity-regulating kinases (MARKS) are serine/threonine kinases that phosphorylate the tubulin-binding domain of MAPs, thereby causing their detachment from microtubules and leading to increased microtubule dynamics (Drewes et al.,  Trends Biochem. Sci.,  1998, 23, 307-311).  
       [0003] The structural MAP family includes the neuronal microtubule associated proteins tau and MAP2, as well as MAP4, which is present in all non-neuronal vertebrate cells. The tau protein is particularly well-studied because phosphorylation of tau at a single residue, Ser-262, dramatically reduced microtubule binding, and phosphorylation of Ser-262 is elevated in tau isolated from the neurofibrillary tangles of Alzheimer&#39;s disease. It is believed that the neuronal pathology of this disease may be due to a loss of the ability of tau to bind microtubules. A major kinase activity that phosphorylated the neuronal MAPs tau and MAP2, as well as the ubiquitous MAP4, and which caused rapid detachment of all three MAPs from microtubules and resulted in dynamic instability, was purified, and this lead to the identification of the first MARK protein (Drewes et al.,  Cell,  1997, 89, 297-308). A family of four related genes, MARK1-4, has since been identified (Drewes et al.,  Trends Biochem. Sci.,  1998, 23, 307-311).  
       [0004] Because of their involvement in MAP activity and microtubule functions such as cellular morphogenesis and the generation and/or maintenance of cell polarity, the MARK proteins can also serve as markers of differentiating cells (Drewes et al.,  Trends Biochem. Sci.,  1998, 23, 307-311). MARK3 was originally identified as such a marker. In a study of the multiphasic process of human pancreas carcinogenesis, a panel of monoclonal antibodies was developed and used for the detection and characterization of tumorigenic stage. One antibody in this panel had a strong affinity for a membrane-associated protein of 78 kDa which was found to mislocalize in and eventually be lost from tumor cells. Carcinogenesis in fetal pancreas cells is associated with a loss of epithelial polarity, and a loss of this marker correlates with the tumorigenic phenotype (Parsa,  Cancer Res.,  1988, 48, 2265-2272). This p78 marker present in normal and nontumorigenic cells, but absent from tumorigenic cells and primary carcinomas of human pancreas, was later found to bear homology to the MARK kinases involved in specific phosphorylation of MAPs, and was thus called MARK3 (also known as MAP/microtubule affinity-regulating kinase 3, microtubule-associated protein/microtubule affinity-regulating kinase 3, Cdc25C-associated protein kinase 1, CTAK1, c-TAK1, C-Takl, Cdc twenty-five C associated protein kinase, ELKL motif kinase 2 long form, Emk2, and ETK-1) (Drewes et al.,  Trends Biochem. Sci.,  1998, 23, 307-311; Ono et al.,  Cytogenet. Cell Genet.,  1997, 79, 101-102).  
       [0005] Independently, the rat MARK3 protein was purified as the Cdc25C-associated protein kinase, CTAK1, suggesting that MARK3 plays a role in cell cycle regulation (Ogg et al.,  J. Biol. Chem.,  1994, 269, 30461-30469). Progression of the eukaryotic cell cycle is controlled by the sequential activation of cyclin-dependent kinases, and human Cdc25C is a dual-specificity protein phosphatase that triggers entry into mitosis by dephosphorylating and thus activating the Cdc2 cyclin-dependent kinase. The Cdc25C phosphatase is itself regulated by phosphorylation, and a Cdc25C-associated protein kinase (MARK3) was isolated from rat liver and found to bind human Cdc25C in vitro and in vivo and to phosphorylate it at Ser-216 (Ogg et al.,  J. Biol. Chem.,  1994, 269, 30461-30469). Purified Cdc25C-associated protein kinase from rat liver was subjected to protein sequencing and two homologous proteins were identified in sequence databases, the human p78 marker protein lost in pancreatic carcinomas, and the murine ELKL motif kinase gene. MARK3 was further characterized to belong to the CaMKII/Snf1/AMPK subfamily of protein kinases which share a conserved N-terminal kinase domain, followed by a divergent C-terminal region of unknown function, and a conserved region of about 40 amino acids at their extreme C-termini which ends in ELKL (glutamate-leucine-lysine-leucine) (Peng et al.,  Cell Growth Differ.,  1998, 9, 197-208).  
       [0006] Human CTAK1 (MARK3) was subsequently cloned from a B-cell cDNA library by using primers designed against human p78, and it was discovered that the MARK3 gene undergoes alternative splicing. Northern analysis revealed two transcripts of approximately 3.8 and 3.1 kilobases, expressed in all human tissues examined, and a 3.0 kilobase transcript was observed in heart tissue. Using antibodies, endogenous MARK3 protein was found to localize to the cytoplasm but not the nucleus of HeLa cells. (Peng et al.,  Cell Growth Differ.,  1998, 9, 197-208). The MARK3 gene was mapped by fluorescence in situ hybridization to human chromosomal band 14q32.3 (Ono et al.,  Cytogenet. Cell Genet.,  1997, 79, 101-102).  
       [0007] MARK3 phosphorylates Ser-216 of Cdc25C, and phosphorylation of this residue results in a consensus recognition motif for 14-3-3 proteins. The 14-3-3 proteins are believed to regulate Cdc25C function by binding to Cdc25C and retaining it in the cytoplasmic compartment during interphase. Because MARK3 phosphorylates Ser-216 of Cdc25C and promotes 14-3-3 binding, and Cdc25C remains phosphorylated throughout interphase, Cdc25C/14-3-3 complexes are present throughout interphase. MARK3 is localized to the cytoplasm, and its phosphorylation of Ser-216 of Cdc25C allows 14-3-3 to bind and retain Cdc25C in the cytoplasm, negatively regulating the functional interaction between Cdc25C and the Cdc2/Cyclin B complex during interphase and inhibiting mitotic entry. Thus, one function of the MARK3 kinase in vivo may be to regulate the interactions between important cell cycle regulatory proteins (Dalal et al.,  Mol. Cell. Biol.,  1999, 19, 4465-4479; Peng et al.,  Cell Growth Differ.,  1998, 9, 197-208).  
       [0008] The 14-3-3 binding site within another protein was also found to be a substrate for phosphorylation by MARK3. Binding of the 14-3-3□ protein to protein-tyrosine phosphatase 1 (PTPHl) is greatly enhanced by pretreating PTPH1 with MARK3. In addition to substantiating the hypothesis that MARK3 phosphorylates and regulates 14-3-3 binding sites, this interaction between the MARK3 kinase and PTPH1 indicates a link between serine/threonine and tyrosine phosphorylation-dependent signaling pathways (Zhang et al.,  J. Biol. Chem.,  1997, 272, 27281-27287).  
       [0009] Disclosed and claimed in U.S. Pat. No. 5,863,729 is a DNA sequence encoding the amino acid sequence of MARK3, a transformed cell comprising said DNA sequence combined with a heterologous control sequence for expression in said cell, and a method for detecting and quantifying MARK3 expression in a cell or tissue by hybridizing mRNA with MARK3 DNA probes (Piwnica-Worms, 1999).  
       [0010] Disclosed and claimed in PCT Publication WO 00/73469 is an isolated, enriched, or purified nucleic acid molecule encoding the MARK3 kinase, and a nucleic acid molecule wherein said nucleic acid molecule comprises a nucleotide sequence that is the complement of the MARK3 DNA sequence, and said complementary sequence except that it lacks one or more, but not all, of a domain selected from the group consisting of an N-terminal domain, a catalytic domain, a C-terminal domain, a coiled-coil structure region, a proline-rich region, a spacer region, an insert, and a C-terminal tail. Further claimed is a method for detection of MARK3 in a sample as a diagnostic tool for a disease or disorder, wherein said method comprises contacting said sample with a nucleic acid probe which hybridizes to the MARK3 DNA sequence. Generally disclosed are substances useful for treatment of disorders or diseases that modulate the activity of the polypeptides including antisense oligonucleotides, and transgenic nonhuman mammals containing a antisense nucleic acid transgene for regulating the expression of MARK3 (Plowman et al., 2000).  
       [0011] Currently, there are no known therapeutic agents which effectively inhibit the synthesis of MARK3. Consequently, there remains a long felt need for additional agents capable of effectively inhibiting MARK3 function.  
       [0012] 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 MARK3 expression.  
       [0013] The present invention provides compositions and methods for modulating MARK3 expression.  
       SUMMARY OF THE INVENTION  
       [0014] The present invention is directed to compounds, particularly antisense oligonucleotides, which are targeted to a nucleic acid encoding MARK3, and which modulate the expression of MARK3. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of modulating the expression of MARK3 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 MARK3 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  
       [0015] The present invention employs oligomeric compounds, particularly antisense oligonucleotides, for use in modulating the function of nucleic acid molecules encoding MARK3, ultimately modulating the amount of MARK3 produced. This is accomplished by providing antisense compounds which specifically hybridize with one or more nucleic acids encoding MARK3. As used herein, the terms “target nucleic acid” and “nucleic acid encoding MARK3” encompass DNA encoding MARK3, 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 MARK3. 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.  
       [0016] 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 MARK3. 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 MARK3, regardless of the sequence(s) of such codons.  
       [0017] 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.  
       [0018] 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.  
       [0019] 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.  
       [0020] 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.  
       [0021] 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.  
       [0022] 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.  
       [0023] 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.  
       [0024] 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.  
       [0025] 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).  
       [0026] 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.  
       [0027] 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.  
       [0028] 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.  
       [0029] 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.  
       [0030] 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.  
       [0031] 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.  
       [0032] 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.  
       [0033] 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).  
       [0034] 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.  
       [0035] 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.  
       [0036] 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.  
       [0037] 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.  
       [0038] 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.  
       [0039] 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.  
       [0040] 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.  
       [0041] 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.  
       [0042] 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.  
       [0043] 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.  
       [0044] 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.  
       [0045] 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.  
       [0046] 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.  
       [0047] 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.  
       [0048] 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 ) m O]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, CF 3 , 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.  
       [0049] 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.  
       [0050] 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.  
       [0051] 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.  
       [0052] 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.  
       [0053] 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 triethylammonium 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.  
       [0054] 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.  
       [0055] 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.  
       [0056] 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.  
       [0057] 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.  
       [0058] 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.  
       [0059] 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.  
       [0060] 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.  
       [0061] 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.  
       [0062] 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.  
       [0063] 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.  
       [0064] 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 MARK3 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.  
       [0065] The antisense compounds of the invention are useful for research and diagnostics, because these compounds hybridize to nucleic acids encoding MARK3, 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 MARK3 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 MARK3 in a sample may also be prepared.  
       [0066] 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.  
       [0067] 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.  
       [0068] 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.  
       [0069] 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.  
       [0070] 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.  
       [0071] 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.  
       [0072] 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.  
       [0073] 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.  
       [0074] Emulsions  
       [0075] 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 Am 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.  
       [0076] 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).  
       [0077] 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).  
       [0078] 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.  
       [0079] 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).  
       [0080] 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.  
       [0081] 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.  
       [0082] 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.  
       [0083] 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).  
       [0084] 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.  
       [0085] 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.  
       [0086] 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.  
       [0087] 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.  
       [0088] Liposomes  
       [0089] 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.  
       [0090] 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.  
       [0091] 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.  
       [0092] 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.  
       [0093] 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.  
       [0094] 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.  
       [0095] 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.  
       [0096] 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).  
       [0097] 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).  
       [0098] 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.  
       [0099] 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).  
       [0100] 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).  
       [0101] 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 GM1, 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).  
       [0102] 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.).  
       [0103] 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.  
       [0104] 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.  
       [0105] 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.  
       [0106] 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).  
       [0107] 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.  
       [0108] 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.  
       [0109] 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.  
       [0110] 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.  
       [0111] 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).  
       [0112] Penetration Enhancers  
       [0113] 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.  
       [0114] 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.  
       [0115] 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).  
       [0116] 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).  
       [0117] 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).  
       [0118] 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).  
       [0119] 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).  
       [0120] 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.  
       [0121] 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.  
       [0122] Carriers  
       [0123] 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).  
       [0124] Excipients  
       [0125] 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.).  
       [0126] 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.  
       [0127] 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.  
       [0128] 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.  
       [0129] Other Components  
       [0130] 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.  
       [0131] 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.  
       [0132] 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.  
       [0133] 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.  
       [0134] 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.  
       [0135] 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  
     [0136] Nucleoside Phosphoramidites for Oligonucleotide Synthesis Deoxy and 2′-alkoxy Amidites  
     [0137] 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.  
     [0138] 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).  
     [0139] 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:  
     [0140] Preparation of 5′-O-Dimethoxytrityl-thymidine Intermediate for 5-methyl dC Amidite  
     [0141] 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 L) 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 1 ,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.  
     [0142] Preparation of 5′-O-Dimethoxytrityl-2′-deoxy-5-methylcytidine Intermediate for 5-methyl-dC Amidite  
     [0143] 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).  
     [0144] 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.  
     [0145] 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.  
     [0146] Preparation of 5′-O-Dimethoxytrityl-2′-deoxy-N-4-benzoyl-5-methylcytidine Penultimate Intermediate for 5-methyl dC Amidite  
     [0147] 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.  
     [0148] 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 re-equilibrated 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, co-evaporated 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.  
     [0149] [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N-benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (5-methyl dC Amidite)  
     [0150] 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 g an off-white foam solid (96%).  
     [0151] 2′-Fluoro Amidites  
     [0152] 2′-Fluorodeoxyadenosine Amidites  
     [0153] 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.  
     [0154] 2′-Fluorodeoxyguanosine  
     [0155] 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 isobutyrylarabinofuranosylguanosine. Alternatively, isobutyrylarabinofuranosylguanosine 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.  
     [0156] 2′-Fluorouridine  
     [0157] 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.  
     [0158] 2′-Fluorodeoxycytidine  
     [0159] 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.  
     [0160] 2′-O-(2-Methoxyethyl) Modified Amidites  
     [0161] 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).  
     [0162] Preparation of 2′-O-(2-methoxyethyl)-5-methyluridine Intermediate  
     [0163] 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.  
     [0164] 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.).  
     [0165] 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.  
     [0166] Preparation of 5′-O-DMT-2′-O-(2-methoxyethyl)-5-methyluridine Penultimate Intermediate  
     [0167] 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.  
     [0168] 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.  
     [0169] Preparation of [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-5-methyluridin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE T Amidite)  
     [0170] 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%).  
     [0171] Preparation of 5′-O-Dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methylcytidine Intermediate  
     [0172] 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  
     [0173] 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.  
     [0174] Preparation of 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-N-4-benzoyl-5-methyl-cytidine Penultimate Intermediate:  
     [0175] 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%.  
     [0176] 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)  
     [0177] 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&gt;. 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%).  
     [0178] 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)  
     [0179] 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%).  
     [0180] 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)  
     [0181] 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%).  
     [0182] 2′-O-(Aminooxyethyl) Nucleoside Amidites and 2′-O-(dimethylaminooxyethyl) Nucleoside Amidites  
     [0183] 2′-(Dimethylaminooxyethoxy) Nucleoside Amidites  
     [0184] 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.  
     [0185] 5′-O-tert-Butyldiphenylsilyl-O 2 -2′-anhydro-5-methyluridine  
     [0186] 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.  
     [0187] 5′-O-tert-Butyldiphenylsilyl-2′-O-(2-hydroxyethyl)-5-methyluridine  
     [0188] 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.  
     [0189] 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine  
     [0190] 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-butyldiphenylsilyl-5-methyluridine as white foam (21.819 g, 86%) upon rotary evaporation.  
     [0191] 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy)ethyl]-5-methyluridine  
     [0192] 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.  
     [0193] 5′-O-tert-Butyldiphenylsilyl-2′-O-[N,N dimethylaminooxyethyl]-5-methyluridine  
     [0194] 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.  
     [0195] 2′-O-(dimethylaminooxyethyl)-5-methyluridine  
     [0196] 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.  
     [0197] 5′-O-DMT-2′-O-(dimethylaminooxyethyl)-5-methyluridine  
     [0198] 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.  
     [0199] 5′-O-DMT-2 1 -O-(2-N,N-dimethylaminooxyethyl)-5-methyluridine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] 
     [0200] 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.  
     [0201] 2′-(Aminooxyethoxy) Nucleoside Amidites  
     [0202] 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.  
     [0203] N2-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite] 
     [0204] 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 aminor 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 Al 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].  
     [0205] 2′-dimethylaminoethoxyethoxy (2′-DMAEOE) Nucleoside Amidites  
     [0206] 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.  
     [0207] 2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl]-5-methyl Uridine  
     [0208] 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.  
     [0209] 5′-O-dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy) ethyl)]-5-methyl Uridine  
     [0210] To 0.5 g (1.3 mmol) of 2′-O-[2(2-N,N-dimethylamino-ethoxy)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.  
     [0211] 5′-O-Dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)-ethyl)]-5-methyl uridine-3′-O-(cyanoethyl-N,N-diisopropyl)phosphoramidite  
     [0212] 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  
     [0213] Oligonucleotide Synthesis  
     [0214] 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.  
     [0215] 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.  
     [0216] Alkyl phosphonate oligonucleotides are prepared as described in U.S. Pat. No. 4,469,863, herein incorporated by reference.  
     [0217] 3′-Deoxy-3′-methylene phosphonate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,610,289 or 5,625,050, herein incorporated by reference.  
     [0218] Phosphoramidite oligonucleotides are prepared as described in U.S. Pat. No. 5,256,775 or U.S. Pat. No. 5,366,878, herein incorporated by reference.  
     [0219] 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. 3′-Deoxy-3′-amino phosphoramidate oligonucleotides are prepared as described in U.S. Pat. No. 5,476,925, herein incorporated by reference.  
     [0220] Phosphotriester oligonucleotides are prepared as described in U.S. Pat. No. 5,023,243, herein incorporated by reference.  
     [0221] 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  
     [0222] Oligonucleoside Synthesis  
     [0223] 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.  
     [0224] 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.  
     [0225] Ethylene oxide linked oligonucleosides are prepared as described in U.S. Pat. No. 5,223,618, herein incorporated by reference.  
     Example 4  
     [0226] PNA Synthesis  
     [0227] 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  
     [0228] Synthesis of Chimeric Oligonucleotides  
     [0229] 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”.  
     [0230] [2′-O-Me]-[2′-deoxy]-[2′-O-Me] Chimeric Phosphorothioate Oligonucleotides  
     [0231] 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.  
     [0232] [2′-O-(2-Methoxyethyl)]-[2′-deoxy]-[2′-O-(Methoxyethyl)] Chimeric Phosphorothioate Oligonucleotides  
     [0233] [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.  
     [0234] [2′-O-(2-Methoxyethyl)Phosphodiester]-[2′-deoxy Phosphorothioate]-[2′-O-(2-Methoxyethyl) Phosphodiester] Chimeric Oligonucleotides  
     [0235] [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.  
     [0236] 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  
     [0237] oligonucleotide Isolation  
     [0238] 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  
     [0239] Oligonucleotide Synthesis—96 Well Plate Format  
     [0240] 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.  
     [0241] 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  
     [0242] Oligonucleotide Analysis—96-Well Plate Format  
     [0243] 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  
     [0244] Cell Culture and Oligonucleotide Treatment  
     [0245] 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.  
     [0246] T-24 Cells:  
     [0247] 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.  
     [0248] 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.  
     [0249] A549 Cells:  
     [0250] 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.  
     [0251] NHDF Cells:  
     [0252] 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.  
     [0253] HEK Cells:  
     [0254] 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.  
     [0255] Treatment with Antisense Compounds:  
     [0256] 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.  
     [0257] 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  
     [0258] Analysis of Oligonucleotide Inhibition of MARK3 Expression  
     [0259] Antisense modulation of MARK3 expression can be assayed in a variety of ways known in the art. For example, MARK3 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.  
     [0260] Protein levels of MARK3 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 MARK3 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).  
     [0261] 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  
     [0262] 15 Poly(A)+ mRNA Isolation  
     [0263] 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.  
     [0264] Cells grown on 100 mm or other standard plates may be treated similarly, using appropriate volumes of all solutions.  
     Example 12  
     [0265] Total RNA Isolation  
     [0266] 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 RWl 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.  
     [0267] 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  
     [0268] Real-Time Quantitative PCR Analysis of MARK3 mRNA Levels  
     [0269] Quantitation of MARK3 mRNA levels was determined by real-time quantitative PCR using the ABI PRISMM 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.  
     [0270] 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.  
     [0271] 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 nM 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).  
     [0272] 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 RiboGreenTM (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 RiboGreenTM RNA quantification reagent from Molecular Probes. Methods of RNA quantification by RiboGreenTM are taught in Jones, L. J., et al, (Analytical Biochemistry, 1998, 265, 368-374).  
     [0273] In this assay, 170 μL of RiboGreenTM working reagent (RiboGreenTM 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.  
     [0274] Probes and primers to human MARK3 were designed to hybridize to a human MARK3 sequence, using published sequence information (GenBank accession number U64205.1, incorporated herein as SEQ ID NO:4). For human MARK3 the PCR primers were:  
     [0275] forward primer: TGACCATGCTGGACCAGCTA (SEQ ID NO: 5)  
     [0276] reverse primer: TCACCATCTGCAGTGCTTGTCT (SEQ ID NO: 6) and the  
     [0277] PCR probe was: FAM-CCTTCTGTTGTGGCGTATCCGAAAAGGA-TAMRA (SEQ ID NO: 7) where FAM is the fluorescent dye and TAMRA is the quencher dye. For human GAPDH the PCR primers were:  
     [0278] forward primer: GAAGGTGAAGGTCGGAGTC(SEQ ID NO:8)  
     [0279] reverse primer: GAAGATGGTGATGGGATTTC (SEQ ID NO:9) and the  
     [0280] 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  
     [0281] Northern Blot Analysis of MARK3 mRNA Levels  
     [0282] 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.  
     [0283] To detect human MARK3, a human MARK3 specific probe was prepared by PCR using the forward primer TGACCATGCTGGACCAGCTA (SEQ ID NO: 5) and the reverse primer TCACCATCTGCAGTGCTTGTCT (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.).  
     [0284] 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  
     [0285] Antisense Inhibition of Human MARK3 Expression by Chimeric Phosphorothioate Oligonucleotides Having 2′-MOE Wings and a Deoxy Gap  
     [0286] In accordance with the present invention, a series of oligonucleotides were designed to target different regions of the human MARK3 RNA, using published sequences (GenBank accession number U64205.1, incorporated herein as SEQ ID NO: 4, GenBank accession number NM — 002376.1, incorporated herein as SEQ ID NO: 11, GenBank accession number AF159295.1, incorporated herein as SEQ ID NO: 12, GenBank accession number BF083244.1, incorporated herein as SEQ ID NO: 13, GenBank accession number AF170723.1, incorporated herein as SEQ ID NO: 14, and a genomic sequence representing nucleotides 177000-296500 of GenBank accession number NT — 028360.1, the complement of which is incorporated herein as SEQ ID NO: 15). 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 MARK3 mRNA levels by quantitative real-time PCR as described in other examples herein. Data are averages from two experiments in which T-24 cells 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 MARK3 mRNA levels by chimeric       phosphorothioate oligonucleotides having 2′-MOE wings and a       deoxy gap                                                     TARGET                   CONTROL               SEQ ID   TARGET       %   SEQ   SEQ ID       ISIS #   REGION   NO   SITE   SEQUENCE   INHIB   ID NO   NO                                                     151465   Coding   4   398   gtctcgttcattcaccgttg   11   16   2               151466   Coding   4   1814   gcgttcaggaatatccgcct   19   17   2               151467   Coding   4   2040   gactggcagtgcctcttggg   71   18   2               151468   Coding   4   2168   gagattagtggagcctcggc   89   19   2               151469   Coding   4   896   cttgaggtctcgatgtacga   77   20   2               151470   Coding   4   2155   cctcggcttcgagtctggga   95   21   2               151471   Coding   4   498   ctgcacaggaggctatagag   68   22   2               151472   Coding   4   1792   ttaggattacttgcattccc   98   23   2               151473   Coding   4   1665   gactccttttcggatacgcc   79   24   2               151474   5′UTR   4   345   ttaattctgcacaatgcgag   91   25   2               151475   Coding   4   590   tgtaaggatatgtcttgcca   35   26   2               151476   5′UTR   4   341   ttctgcacaatgcgagggtc   75   27   2               151477   Coding   4   1977   ttgaagcaactggagttctc   22   28   2               151478   Coding   4   500   atctgcacaggaggctatag   56   29   2               151479   3′UTR   4   2590   gaaaacactttacttgctac   25   30   2               151480   Coding   4   2134   aatggtgtggcttcatggga   75   31   2               151481   Coding   4   988   gtgtcgagtttaccgccaac   83   32   2               151482   Coding   4   1868   tcgtgtcattccaccagatg   91   33   2               151483   Coding   4   1762   ctggctggagcaattccctt   50   34   2               151484   Coding   4   1345   ttttggtctgagatgtctag   74   35   2               151485   Coding   4   1899   tagttctctcactgcaaaca   51   36   2               151486   Coding   4   2224   ttttgctcagcagatacatt   28   37   2               151487   Coding   4   495   cacaggaggctatagagttt   82   38   2               151488   5′UTR   4   218   ccgttctagatcccgggcct   62   39   2               151489   Coding   4   2050   aaagtgctacgactggcagt   12   40   2               151490   Coding   4   795   gtgcaaccaaatagtcaaat   65   41   2               151491   3′UTR   4   2600   cagtgttcaggaaaacactt   12   42   2               151492   Coding   4   550   cccttgccgattgttttcaa   68   43   2               151493   Coding   4   1296   cttcttcatgccctgcattg   83   44   2               151494   Coding   4   469   cgagctcctgagcggctggt   91   45   2               151495   Coding   4   1233   ttggatttagcaccaggaaa   70   46   2               151496   Coding   4   1998   ctgcactactgatactgtgt   87   47   2               151497   Coding   4   1877   agtatttcgtcgtgtcattc   69   48   2               151498   Coding   4   1090   gtgtataaaatgacccccag   79   49   2               151499   Coding   4   1829   agtggagcttttcttgcgtt   70   50   2               151500   Coding   4   2208   cattgcgactccttgtgagt   59   51   2               151501   Coding   4   647   tagacttgttggattcaact   5   52   2               199661   Start   4   367   ctagtggacattttactgca   72   53   2           Codon               199662   Coding   4   609   ttattgcaacctctctgcct   36   54   2               199663   Coding   4   663   ctctgaagagcttttgtaga   50   55   2               199664   Coding   4   1476   tagcatccagctctgaagat   0   56   2               199665   Coding   4   1848   ctgtgttactactagggaca   67   57   2               199666   Stop   4   2555   atcactgggttacagcttta   63   58   2           Codon               199667   Coding   11   1272   tcggcctaacctctgaagat   0   59   2               199668   3′UTR   11   2488   ggttgcacatctttaatgta   10   60   2               199669   3′UTR   11   2647   ggtactagtaatgactggct   23   61   2               199670   3′UTR   11   2663   gatgatctcccgcagaggta   10   62   2               199671   5′UTR   12   363   gatgcccttagatgtccggg   0   63   2               199672   5′UTR   12   393   ccacccgagattgagcaata   0   64   2               199673   5′UTR   12   562   gatagctctttctcgattcc   9   65   2               199674   5′UTR   12   719   ggaaaccaaagtctttgggt   0   66   2               199675   Coding   12   1977   cttgacaaccctgtctaaat   0   67   2               199676   Coding   12   2049   ctgcagacacaataaatgta   0   68   2               199677   intron   13   12   gtttagttaaccaaacacga   0   69   2               199678   intron   13   21   cacctttaggtttagttaac   0   70   2               199679   intron:   13   67   ctctcagttcctttggagag   35   71   2           exon           junction               199680   exon:   13   187   acatgattacctctagagtg   46   72   2           intron           junction               199681   intron   13   263   ccagtatggcatacaaatca   55   73   2               199682   intron   13   385   tctgataaccgtaatattta   0   74   2               199683   exon:   14   890   tgacatgtttctccttgtga   22   75   2           exon           junction               199684   exon:   14   917   agttggaagccttttgataa   0   76   2           exon           junction               199685   exon:   14   926   ctcatattcagttggaagcc   67   77   2           exon           junction               199686   exon:   14   957   tgcgacttgagccctcatat   37   78   2           exon           junction               199687   exon:   14   962   tacattgcgacttgagccct   20   79 2           exon           junction               199688   intron   15   25265   attgtgttacagcagcaaaa   62   80   2               199689   intron   15   61215   gacacatttttgtgcacctg   72   81   2               199690   intron:   15   72274   aatacttcacctataggtga   4   82   2           exon           junction               199691   intron   15   74052   gagaagttaaatgatagcca   21   83   2               199692   intron:   15   77537   cagacacaatctgaatagga   7   84   2           exon           junction               199693   intron:   15   83213   tcggcctaaccttagcaagt   71   85   2           exon           junction               199694   intron   15   101800   atcacaatggtctacatata   41   86   2               199695   intron:   15   106909   aggaatagtgctatgagatc   21   87   2           exon           junction                  
 
     [0287] As shown in Table 1, SEQ ID NOs 18, 19, 20, 21, 22, 23, 24, 25, 27, 29, 31, 32, 33, 35, 38, 39, 41, 43, 44, 45, 46, 47, 48, 49, 50, 51, 53, 57, 58, 73, 77, 80, 81 and 85 demonstrated at least 55% inhibition of human MARK3 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 MARK3.                                             TARGET           REV               SITE   SEQ ID   TARGET       COMP OF       SEQ ID       ID   NO   SITE   SEQUENCE   SEQ ID   ACTIVE IN   NO                                                 66987   4   2040   cccaagaggcactgccagtc   18     H. sapiens     88               66988   4   2168   gccgaggctccactaatctc   19     H. sapiens     89               66989   4   896   tcgtacatcgagacctcaag   20     H. sapiens     90               66990   4   2155   tcccagactcgaagccgagg   21     H. sapiens     91               66991   4   498   ctctatagcctcctgtgcag   22     H. sapiens     92               66992   4   1792   gggaatgcaagtaatcctaa   23     H. sapiens     93               66993   4   1665   ggcgtatccgaaaaggagtc   24     H. sapiens     94               66994   4   345   ctcgcattgtgcagaattaa   25     H. sapiens     95               66996   4   341   gaccctcgcattgtgcagaa   27     H. sapiens     96               66998   4   500   ctatagcctcctgtgcagat   29     H. sapiens     97               67000   4   2134   tcccatgaagccacaccatt   31     H. sapiens     98               67001   4   988   gttggcggtaaactcgacac   32     H. sapiens     99               67002   4   1868   catctggtggaatgacacga   33     H. sapiens     100               67004   4   1345   ctagacatctcagaccaaaa   35     H. sapiens     101               67007   4   495   aaactctatagcctcctgtg   38     H. sapiens     102               67008   4   218   aggcccgggatctagaacgg   39     H. sapiens     103               67010   4   795   atttgactatttggttgcac   41     H. sapiens     104               67012   4   550   ttgaaaacaatcggcaaggg   43     H. sapiens     105               67013   4   1296   caatgcagggcatgaagaag   44     H. sapiens     106               67014   4   469   accagccgctcaggagctcg   45     H. sapiens     107               67015   4   1233   tttcctggtgctaaatccaa   46     H. sapiens     108               67016   4   1998   acacagtatcagtagtgcag   47     H. sapiens     109               67017   4   1877   gaatgacacgacgaaatact   48     H. sapiens     110               67018   4   1090   ctgggggtcattttatacac   49     H. sapiens     111               67019   4   1829   aacgcaagaaaagctccact   50     H. sapiens     112               67020   4   2208   actcacaaggagtcgcaatg   51     H. sapiens     113               117395   4   367   tgcagtaaaatgtccactag   53     H. sapiens     114               117399   4   1848   tgtccctagtagtaacacag   57     H. sapiens     115               117400   4   2555   taaagctgtaacccagtgat   58     H. sapiens     116               117415   13   263   tgatttgtatgccatactgg   73     H. sapiens     117               117419   14   926   ggcttccaactgaatatgag   77     H. sapiens     118               117422   15   25265   ttttgctgctgtaacacaat   80     H. sapiens     119               117423   15   61215   caggtgcacaaaaatgtgtc   81     H. sapiens     120               117427   15   83213   acttgctaaggttaggccga   85     H. sapiens     121                  
 
     [0288] 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 MARK3.  
     [0289] 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 MARK3 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 MARK3 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 MARK3. Once it is shown that the candidate antisense compound or compounds are capable of inhibiting the expression of a nucleic acid molecule encoding MARK3, the candidate antisense compound may be employed as an antisense compound in accordance with the present invention.  
     [0290] 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  
     [0291] Western Blot Analysis of MARK3 Protein Levels  
     [0292] 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 MARK3 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 
         
           
             121  
           
           
             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  
             2698  
             DNA  
             H. sapiens  
             
 
             
               CDS  
               (376)...(2565)  
             
           
            4 

gagctgaaat tcgcggtgcg acgggaggga gtggagaagg aggtgagggg gcccaggatc     60 

gcggggcgcc ctgaggcaag gggacgccgg tgggtcgaag cgcagcccgc cgcccgcagg    120 

ctcggctccg ccactgccgc cctcccggtc tcctcgcctc gggcgccgag gcagggagag    180 

aatgagcccc gggacccgcc gggggacggc ccgggccagg cccgggatct agaacggccg    240 

tagggggaag ggagccgccc tccccacggc gccttttcgg aactgccgtg gactcgagga    300 

cgctggtcgc cggcctccta gggctgtgct gttttgtttt gaccctcgca ttgtgcagaa    360 

ttaaagtgca gtaaa atg tcc act agg acc cca ttg cca acg gtg aat gaa     411 
                 Met Ser Thr Arg Thr Pro Leu Pro Thr Val Asn Glu 
                   1               5                  10 

cga gac act gaa aac cac acg tca cat gga gat ggg cgt caa gaa gtt      459 
Arg Asp Thr Glu Asn His Thr Ser His Gly Asp Gly Arg Gln Glu Val 
         15                  20                  25 

acc tct cgt acc agc cgc tca gga gct cgg tgt aga aac tct ata gcc      507 
Thr Ser Arg Thr Ser Arg Ser Gly Ala Arg Cys Arg Asn Ser Ile Ala 
     30                  35                  40 

tcc tgt gca gat gaa caa cct cac atc gga aac tac aga ctg ttg aaa      555 
Ser Cys Ala Asp Glu Gln Pro His Ile Gly Asn Tyr Arg Leu Leu Lys 
 45                  50                  55                  60 

aca atc ggc aag ggg aat ttt gca aaa gta aaa ttg gca aga cat atc      603 
Thr Ile Gly Lys Gly Asn Phe Ala Lys Val Lys Leu Ala Arg His Ile 
                 65                  70                  75 

ctt aca ggc aga gag gtt gca ata aaa ata att gac aaa act cag ttg      651 
Leu Thr Gly Arg Glu Val Ala Ile Lys Ile Ile Asp Lys Thr Gln Leu 
             80                  85                  90 

aat cca aca agt cta caa aag ctc ttc aga gaa gta aga ata atg aag      699 
Asn Pro Thr Ser Leu Gln Lys Leu Phe Arg Glu Val Arg Ile Met Lys 
         95                 100                 105 

att tta aat cat ccc aat ata gtg aag tta ttc gaa gtc att gaa act      747 
Ile Leu Asn His Pro Asn Ile Val Lys Leu Phe Glu Val Ile Glu Thr 
    110                 115                 120 

gaa aaa aca ctc tac cta atc atg gaa tat gca agt gga ggt gaa gta      795 
Glu Lys Thr Leu Tyr Leu Ile Met Glu Tyr Ala Ser Gly Gly Glu Val 
125                 130                 135                 140 

ttt gac tat ttg gtt gca cat ggc agg atg aag gaa aaa gaa gca aga      843 
Phe Asp Tyr Leu Val Ala His Gly Arg Met Lys Glu Lys Glu Ala Arg 
                145                 150                 155 

tct aaa ttt aga cag att gtg tct gca gtt caa tac tgc cat cag aaa      891 
Ser Lys Phe Arg Gln Ile Val Ser Ala Val Gln Tyr Cys His Gln Lys 
            160                 165                 170 

cgg atc gta cat cga gac ctc aag gct gaa aat cta ttg tta gat gcc      939 
Arg Ile Val His Arg Asp Leu Lys Ala Glu Asn Leu Leu Leu Asp Ala 
        175                 180                 185 

gat atg aac att aaa ata gca gat ttc ggt ttt agc aat gaa ttt act      987 
Asp Met Asn Ile Lys Ile Ala Asp Phe Gly Phe Ser Asn Glu Phe Thr 
    190                 195                 200 

gtt ggc ggt aaa ctc gac acg ttt tgt ggc agt cct cca tac gca gca     1035 
Val Gly Gly Lys Leu Asp Thr Phe Cys Gly Ser Pro Pro Tyr Ala Ala 
205                 210                 215                 220 

cct gag ctc ttc cag ggc aag aaa tat gac ggg cca gaa gtg gat gtg     1083 
Pro Glu Leu Phe Gln Gly Lys Lys Tyr Asp Gly Pro Glu Val Asp Val 
                225                 230                 235 

tgg agt ctg ggg gtc att tta tac aca cta gtc agt ggc tca ctt ccc     1131 
Trp Ser Leu Gly Val Ile Leu Tyr Thr Leu Val Ser Gly Ser Leu Pro 
            240                 245                 250 

ttt gat ggg caa aac cta aag gaa ctg aga gag aga gta tta aga ggg     1179 
Phe Asp Gly Gln Asn Leu Lys Glu Leu Arg Glu Arg Val Leu Arg Gly 
        255                 260                 265 

aaa tac aga att ccc ttc tac atg tct aca gac tgt gaa aac ctt ctc     1227 
Lys Tyr Arg Ile Pro Phe Tyr Met Ser Thr Asp Cys Glu Asn Leu Leu 
    270                 275                 280 

aaa cgt ttc ctg gtg cta aat cca att aaa cgc ggc act cta gag caa     1275 
Lys Arg Phe Leu Val Leu Asn Pro Ile Lys Arg Gly Thr Leu Glu Gln 
285                 290                 295                 300 

atc atg aag gac agg tgg atc aat gca ggg cat gaa gaa gat gaa ctc     1323 
Ile Met Lys Asp Arg Trp Ile Asn Ala Gly His Glu Glu Asp Glu Leu 
                305                 310                 315 

aaa cca ttt gtt gaa cca gag cta gac atc tca gac caa aaa aga ata     1371 
Lys Pro Phe Val Glu Pro Glu Leu Asp Ile Ser Asp Gln Lys Arg Ile 
            320                 325                 330 

gat att atg gtg gga atg gga tat tca caa gaa gaa att caa gaa tct     1419 
Asp Ile Met Val Gly Met Gly Tyr Ser Gln Glu Glu Ile Gln Glu Ser 
        335                 340                 345 

ctt agt aag atg aaa tac gat gaa atc aca gct aca tat ttg tta ttg     1467 
Leu Ser Lys Met Lys Tyr Asp Glu Ile Thr Ala Thr Tyr Leu Leu Leu 
    350                 355                 360 

ggg aga aaa tct tca gag ctg gat gct agt gat tcc agt tct agc agc     1515 
Gly Arg Lys Ser Ser Glu Leu Asp Ala Ser Asp Ser Ser Ser Ser Ser 
365                 370                 375                 380 

aat ctt tca ctt gct aag gtt agg ccg agc agt gat ctc aac aac agt     1563 
Asn Leu Ser Leu Ala Lys Val Arg Pro Ser Ser Asp Leu Asn Asn Ser 
                385                 390                 395 

act ggc cag tct cct cac cac aaa gtg cag aga agt gtt tct tca agc     1611 
Thr Gly Gln Ser Pro His His Lys Val Gln Arg Ser Val Ser Ser Ser 
            400                 405                 410 

caa aag caa aga cgc tac agt gac cat gct gga cca gct att cct tct     1659 
Gln Lys Gln Arg Arg Tyr Ser Asp His Ala Gly Pro Ala Ile Pro Ser 
        415                 420                 425 

gtt gtg gcg tat ccg aaa agg agt cag aca agc act gca gat ggt gac     1707 
Val Val Ala Tyr Pro Lys Arg Ser Gln Thr Ser Thr Ala Asp Gly Asp 
    430                 435                 440 

ctc aaa gaa gat gga att tcc tcc cgg aaa tca agt ggc agt gct gtt     1755 
Leu Lys Glu Asp Gly Ile Ser Ser Arg Lys Ser Ser Gly Ser Ala Val 
445                 450                 455                 460 

gga gga aag gga att gct cca gcc agt ccc atg ctt ggg aat gca agt     1803 
Gly Gly Lys Gly Ile Ala Pro Ala Ser Pro Met Leu Gly Asn Ala Ser 
                465                 470                 475 

aat cct aat aag gcg gat att cct gaa cgc aag aaa agc tcc act gtc     1851 
Asn Pro Asn Lys Ala Asp Ile Pro Glu Arg Lys Lys Ser Ser Thr Val 
            480                 485                 490 

cct agt agt aac aca gca tct ggt gga atg aca cga cga aat act tat     1899 
Pro Ser Ser Asn Thr Ala Ser Gly Gly Met Thr Arg Arg Asn Thr Tyr 
        495                 500                 505 

gtt tgc agt gag aga act aca gct gat aga cac tca gtg att cag aat     1947 
Val Cys Ser Glu Arg Thr Thr Ala Asp Arg His Ser Val Ile Gln Asn 
    510                 515                 520 

ggc aaa gaa aac agc act att cct gat cag aga act cca gtt gct tca     1995 
Gly Lys Glu Asn Ser Thr Ile Pro Asp Gln Arg Thr Pro Val Ala Ser 
525                 530                 535                 540 

aca cac agt atc agt agt gca gcc acc cca gat cga atc cgc ttc cca     2043 
Thr His Ser Ile Ser Ser Ala Ala Thr Pro Asp Arg Ile Arg Phe Pro 
                545                 550                 555 

aga ggc act gcc agt cgt agc act ttc cac ggc cag ccc cgg gaa cgg     2091 
Arg Gly Thr Ala Ser Arg Ser Thr Phe His Gly Gln Pro Arg Glu Arg 
            560                 565                 570 

cga acc gca aca tat aat ggc cct cct gcc tct ccc agc ctg tcc cat     2139 
Arg Thr Ala Thr Tyr Asn Gly Pro Pro Ala Ser Pro Ser Leu Ser His 
        575                 580                 585 

gaa gcc aca cca ttg tcc cag act cga agc cga ggc tcc act aat ctc     2187 
Glu Ala Thr Pro Leu Ser Gln Thr Arg Ser Arg Gly Ser Thr Asn Leu 
    590                 595                 600 

ttt agt aaa tta act tca aaa ctc aca agg agt cgc aat gta tct gct     2235 
Phe Ser Lys Leu Thr Ser Lys Leu Thr Arg Ser Arg Asn Val Ser Ala 
605                 610                 615                 620 

gag caa aaa gat gaa aac aaa gaa gca aag cct cga tcc cta cgc ttc     2283 
Glu Gln Lys Asp Glu Asn Lys Glu Ala Lys Pro Arg Ser Leu Arg Phe 
                625                 630                 635 

acc tgg agc atg aaa acc act agt tca atg gat ccc ggg gac atg atg     2331 
Thr Trp Ser Met Lys Thr Thr Ser Ser Met Asp Pro Gly Asp Met Met 
            640                 645                 650 

cgg gaa atc cgc aaa gtg ttg gac gcc aat aac tgc gac tat gag cag     2379 
Arg Glu Ile Arg Lys Val Leu Asp Ala Asn Asn Cys Asp Tyr Glu Gln 
        655                 660                 665 

agg gag cgc ttc ttg ctc ttc tgc gtc cac gga gat ggg cac gcg gag     2427 
Arg Glu Arg Phe Leu Leu Phe Cys Val His Gly Asp Gly His Ala Glu 
    670                 675                 680 

aac ctc gtg cag tgg gaa atg gaa gtg tgc aag ctg cca aga ctg tct     2475 
Asn Leu Val Gln Trp Glu Met Glu Val Cys Lys Leu Pro Arg Leu Ser 
685                 690                 695                 700 

ctg aac ggg gtc cgg ttt aag cgg ata tcg ggg aca tcc ata gcc ttc     2523 
Leu Asn Gly Val Arg Phe Lys Arg Ile Ser Gly Thr Ser Ile Ala Phe 
                705                 710                 715 

aaa aat att gct tcc aaa att gcc aat gag cta aag ctg taa cccagtgatt  2575 
Lys Asn Ile Ala Ser Lys Ile Ala Asn Glu Leu Lys Leu 
            720                 725 

atgatgtaaa ttaagtagca agtaaagtgt tttcctgaac actgatggaa atgtatagaa   2635 

taatatttag gcaataacgt ctgcatcttc taaatcatga aattaaagtc tgaggacgag   2695 

agc                                                                 2698 

 
           
             5  
             20  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            5 

tgaccatgct ggaccagcta                                                 20 

 
           
             6  
             22  
             DNA  
             Artificial Sequence  
             
               PCR Primer  
             
           
            6 

tcaccatctg cagtgcttgt ct                                              22 

 
           
             7  
             28  
             DNA  
             Artificial Sequence  
             
               PCR Probe  
             
           
            7 

ccttctgttg tggcgtatcc gaaaagga                                        28 

 
           
             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  
             2914  
             DNA  
             H. sapiens  
             
 
             
               CDS  
               (172)...(2313)  
             
           
            11 

gacggcccgg gccaggcccg ggatctagaa cggccgtagg gggaagggag ccgccctccc     60 

cacggcgcct tttcggaact gccgtggact cgaggacgct ggtcgccggc ctcctagggc    120 

tgtgctgttt tgttttgacc ctcgcattgt gcagaattaa agtgcagtaa a atg tcc     177 
                                                         Met Ser 
                                                           1 

act agg acc cca ttg cca acg gtg aat gaa cga gac act gaa aac cac      225 
Thr Arg Thr Pro Leu Pro Thr Val Asn Glu Arg Asp Thr Glu Asn His 
          5                  10                  15 

acg tca cat gga gat ggg cgt caa gaa gtt acc tct cgt acc agc cgc      273 
Thr Ser His Gly Asp Gly Arg Gln Glu Val Thr Ser Arg Thr Ser Arg 
     20                  25                  30 

tca gga gct cgg tgt aga aac tct ata gcc tcc tgt gca gat gaa caa      321 
Ser Gly Ala Arg Cys Arg Asn Ser Ile Ala Ser Cys Ala Asp Glu Gln 
 35                  40                  45                  50 

cct cac atc gga aac tac aga ctg ttg aaa aca atc ggc aag ggg aat      369 
Pro His Ile Gly Asn Tyr Arg Leu Leu Lys Thr Ile Gly Lys Gly Asn 
                 55                  60                  65 

ttt gca aaa gta aaa ttg gca aga cat atc ctt aca ggc aga gag gtt      417 
Phe Ala Lys Val Lys Leu Ala Arg His Ile Leu Thr Gly Arg Glu Val 
             70                  75                  80 

gca ata aaa ata att gac aaa act cag ttg aat cca aca agt cta caa      465 
Ala Ile Lys Ile Ile Asp Lys Thr Gln Leu Asn Pro Thr Ser Leu Gln 
         85                  90                  95 

aag ctc ttc aga gaa gta aga ata atg aag att tta aat cat ccc aat      513 
Lys Leu Phe Arg Glu Val Arg Ile Met Lys Ile Leu Asn His Pro Asn 
    100                 105                 110 

ata gtg aag tta ttc gaa gtc att gaa act caa aaa aca ctc tac cta      561 
Ile Val Lys Leu Phe Glu Val Ile Glu Thr Gln Lys Thr Leu Tyr Leu 
115                 120                 125                 130 

atc atg gaa tat gca agt gga ggt aaa gta ttt gac tat ttg gtt gca      609 
Ile Met Glu Tyr Ala Ser Gly Gly Lys Val Phe Asp Tyr Leu Val Ala 
                135                 140                 145 

cat ggc agg atg aag gaa aaa gaa gca aga tct aaa ttt aga cag att      657 
His Gly Arg Met Lys Glu Lys Glu Ala Arg Ser Lys Phe Arg Gln Ile 
            150                 155                 160 

gtg tct gca gtt caa tac tgc cat cag aaa cgg atc gta cat cga gac      705 
Val Ser Ala Val Gln Tyr Cys His Gln Lys Arg Ile Val His Arg Asp 
        165                 170                 175 

ctc aag gct gaa aat cta ttg tta gat gcc gat atg aac att aaa ata      753 
Leu Lys Ala Glu Asn Leu Leu Leu Asp Ala Asp Met Asn Ile Lys Ile 
    180                 185                 190 

gca gat ttc ggt ttt agc aat gaa ttt act gtt ggc ggt aaa ctc gac      801 
Ala Asp Phe Gly Phe Ser Asn Glu Phe Thr Val Gly Gly Lys Leu Asp 
195                 200                 205                 210 

acg ttt tgt ggc agt cct cca tac gca gca cct gag ctc ttc cag ggc      849 
Thr Phe Cys Gly Ser Pro Pro Tyr Ala Ala Pro Glu Leu Phe Gln Gly 
                215                 220                 225 

aag aaa tat gac ggg cca gaa gtg gat gtg tgg agt ctg ggg gtc att      897 
Lys Lys Tyr Asp Gly Pro Glu Val Asp Val Trp Ser Leu Gly Val Ile 
            230                 235                 240 

tta tac aca cta gtc agt ggc tca ctt ccc ttt gat ggg caa aac cta      945 
Leu Tyr Thr Leu Val Ser Gly Ser Leu Pro Phe Asp Gly Gln Asn Leu 
        245                 250                 255 

aag gaa ctg aga gag aga gta tta aga ggg aaa tac aga att ccc ttc      993 
Lys Glu Leu Arg Glu Arg Val Leu Arg Gly Lys Tyr Arg Ile Pro Phe 
    260                 265                 270 

tac atg tct aca gac tgt gaa aac ctt ctc aaa cgt ttc ctg gtg cta     1041 
Tyr Met Ser Thr Asp Cys Glu Asn Leu Leu Lys Arg Phe Leu Val Leu 
275                 280                 285                 290 

aat cca att aaa cgc ggc act cta gag caa atc atg aag gac agg tgg     1089 
Asn Pro Ile Lys Arg Gly Thr Leu Glu Gln Ile Met Lys Asp Arg Trp 
                295                 300                 305 

atc aat gca ggg cat gaa gaa gat gaa ctc aaa cca ttt gtt gaa cca     1137 
Ile Asn Ala Gly His Glu Glu Asp Glu Leu Lys Pro Phe Val Glu Pro 
            310                 315                 320 

gag cta gac atc tca gac caa aaa aga ata gat att atg gtg gga atg     1185 
Glu Leu Asp Ile Ser Asp Gln Lys Arg Ile Asp Ile Met Val Gly Met 
        325                 330                 335 

gga tat tca caa gaa gaa att caa gaa tct ctt agt aag atg aaa tac     1233 
Gly Tyr Ser Gln Glu Glu Ile Gln Glu Ser Leu Ser Lys Met Lys Tyr 
    340                 345                 350 

gat gaa atc aca gct aca tat ttg tta ttg ggg aga aaa tct tca gag     1281 
Asp Glu Ile Thr Ala Thr Tyr Leu Leu Leu Gly Arg Lys Ser Ser Glu 
355                 360                 365                 370 

gtt agg ccg agc agt gat ctc aac aac agt act ggc cag tct cct cac     1329 
Val Arg Pro Ser Ser Asp Leu Asn Asn Ser Thr Gly Gln Ser Pro His 
                375                 380                 385 

cac aaa gtg cag aga agt gtt tct tca agc caa aag caa aga cgc tac     1377 
His Lys Val Gln Arg Ser Val Ser Ser Ser Gln Lys Gln Arg Arg Tyr 
            390                 395                 400 

agt gac cat gct gga cca ggt att cct tct gtt gtg gcg tat ccg aaa     1425 
Ser Asp His Ala Gly Pro Gly Ile Pro Ser Val Val Ala Tyr Pro Lys 
        405                 410                 415 

agg agt cag acc agc act gca gat agt gac ctc aaa gaa gat gga att     1473 
Arg Ser Gln Thr Ser Thr Ala Asp Ser Asp Leu Lys Glu Asp Gly Ile 
    420                 425                 430 

tcc tcc cgg aaa tca act ggc agt gct gtt gga gga aag gga att gct     1521 
Ser Ser Arg Lys Ser Thr Gly Ser Ala Val Gly Gly Lys Gly Ile Ala 
435                 440                 445                 450 

cca gcc agt ccc atg ctt ggg aat gca agt aat cct aat aag gcg gat     1569 
Pro Ala Ser Pro Met Leu Gly Asn Ala Ser Asn Pro Asn Lys Ala Asp 
                455                 460                 465 

att cct gaa cgc aag aaa agc tcc act gtc cct agt agt aac aca gca     1617 
Ile Pro Glu Arg Lys Lys Ser Ser Thr Val Pro Ser Ser Asn Thr Ala 
            470                 475                 480 

tct ggt gga atg aca cga cga aat act tat gtt tgc agt gag aga act     1665 
Ser Gly Gly Met Thr Arg Arg Asn Thr Tyr Val Cys Ser Glu Arg Thr 
        485                 490                 495 

aca gat gat aga cac tca gtg att cag aat ggc aaa gaa aac agc act     1713 
Thr Asp Asp Arg His Ser Val Ile Gln Asn Gly Lys Glu Asn Ser Thr 
    500                 505                 510 

att cct gat cag aga act cca gtt gct tca aca cac agt atc agt agt     1761 
Ile Pro Asp Gln Arg Thr Pro Val Ala Ser Thr His Ser Ile Ser Ser 
515                 520                 525                 530 

gca gcc acc cca gat cga atc cgc ttc cca aga ggc act gcc agt cgt     1809 
Ala Ala Thr Pro Asp Arg Ile Arg Phe Pro Arg Gly Thr Ala Ser Arg 
                535                 540                 545 

agc act ttc cac ggc cag ccc cgg gaa cgg cga acc gca aca tat aat     1857 
Ser Thr Phe His Gly Gln Pro Arg Glu Arg Arg Thr Ala Thr Tyr Asn 
            550                 555                 560 

ggc cct cct gcc tct ccc agc ctg tcc cat gaa gcc aca cca ttg tcc     1905 
Gly Pro Pro Ala Ser Pro Ser Leu Ser His Glu Ala Thr Pro Leu Ser 
        565                 570                 575 

cag act cga agc cga ggc tcc act act ctc ttt agt aaa tta act tca     1953 
Gln Thr Arg Ser Arg Gly Ser Thr Thr Leu Phe Ser Lys Leu Thr Ser 
    580                 585                 590 

aaa ctc aca agg agt cgc aat gta tct gct aag caa aaa gat gaa aac     2001 
Lys Leu Thr Arg Ser Arg Asn Val Ser Ala Lys Gln Lys Asp Glu Asn 
595                 600                 605                 610 

aaa gaa gca aag cct cga tcc cta cgc ttc acc tgg agc atg aaa acc     2049 
Lys Glu Ala Lys Pro Arg Ser Leu Arg Phe Thr Trp Ser Met Lys Thr 
                615                 620                 625 

act agt tca atg gat ccc ggg gac atg atg cgg gaa atc cgc aaa gtg     2097 
Thr Ser Ser Met Asp Pro Gly Asp Met Met Arg Glu Ile Arg Lys Val 
            630                 635                 640 

ttg gac gcc aat aac tgc gac tat gag cag agg gag cgc ttc ttg ctc     2145 
Leu Asp Ala Asn Asn Cys Asp Tyr Glu Gln Arg Glu Arg Phe Leu Leu 
        645                 650                 655 

ttc tgc gtc cac gga gat ggg cac gcg gag aac ctc gtg cag tgg gaa     2193 
Phe Cys Val His Gly Asp Gly His Ala Glu Asn Leu Val Gln Trp Glu 
    660                 665                 670 

atg gaa gtg tgc aag ctg cca aga ctg tct ctg aac ggg gtc cgg ttt     2241 
Met Glu Val Cys Lys Leu Pro Arg Leu Ser Leu Asn Gly Val Arg Phe 
675                 680                 685                 690 

aag cgg ata tcg ggg aca tcc ata gcc ttc aaa aat att gct tcc aaa     2289 
Lys Arg Ile Ser Gly Thr Ser Ile Ala Phe Lys Asn Ile Ala Ser Lys 
                695                 700                 705 

att gcc aat gag cta aag ctg taa cccagtgatt atgatgtaaa ttaagtagca    2343 
Ile Ala Asn Glu Leu Lys Leu 
            710 

agtaaagtgt tttcctgaac actgatggaa atgtatagaa taatatttag gcaataacgt   2403 

ctgcatcttc taaatcatga aattaaagtc tgaggacgag agcacgcctg ggagcgaaag   2463 

ctggcctttt ttctacgaat gcactacatt aaagatgtgc aacctatgcg ccccctgccc   2523 

tacttccgtt accctgagag tcggcgtgtg gccccatctc catgtgcctc ccgtctgggt   2583 

gggtgtgaga gtggacggta tgtgtgtgaa gtggtgtata tggaagcatc tccctacact   2643 

ggcagccagt cattactagt acctctgcgg gagatcatcc ggtgctaaaa cattacagtt   2703 

gccaaggagg aaaatactga atgactgcta agaattaacc ttaagaccag ttcatagtta   2763 

atacaggttt acagttcatg cctgtggttt tgtgtttgtt gttttgtgtt tttttagtgc   2823 

aaaaggttta aatttatagt tgtgaacatt gcttgtgtgt gtttttctaa gtagattcac   2883 

aagataatta aaaattcact ttttctcagg t                                  2914 

 
           
             12  
             3895  
             DNA  
             H. sapiens  
             
 
             
               CDS  
               (1504)...(3762)  
             
           
            12 

ctgcaggaat tccgatcctt ccgcaggttc acctacggaa accttgttac gacttttact     60 

tcctctagat agtcaagttc gaccgtcttc tcagcgctcc gccagggccg tgggccgacc    120 

ccggcggggc cgatccgagg gcctcactaa accatccaat cggtagtagc gacgggcggt    180 

gtgtacaaag ggcagggact taatcaacgc aagcttatga cccgcactta ctgggaattc    240 

ctcgttcatg gggaataatt gcaatccccg atccccatca cgaatggggt tcaacgggtt    300 

acccgcgcct gccggcgtag ggtaggcaca cgctgagcca gtcagtgtag cgcgcgtgca    360 

gccccggaca tctaagggca tcacagacct gttattgctc aatctcgggt ggctgaacgc    420 

cacttgtccc tctaagaagt tgggggacgc cgaccgctcg ggggtcgcgt aactagttag    480 

catgccagag tctcgttcgt tatcggaatt aaccagacaa atcgctccac caactaagaa    540 

cggccatgca ccaccaccca cggaatcgag aaagagctat caatctgtca atcctgtccg    600 

tgtccgggcc gggtgaggtt tcccgtgttg agtcaaatta agccgcaggc tccactcctg    660 

gtggtgccct tccgtcaatt cctttaagtt tcagctttgc aaccatactc cccccggaac    720 

ccaaagactt tggtttcccg gaagctgccc ggcgggtcat gggaataacg ccgccgcatc    780 

gccggtcggc atcgtttatg gtcggaacta cgacggtatc tgatcgtctt cgaacctccg    840 

actttcgttc ttgattaatg aaaacattct tggcaaatgc tttcgctctg gtccgtcttg    900 

cgccggtcca agaatttcgg aattccgcag cggcggccag cagggcggag gctgaggcag    960 

caagctcgct agagagggag aagcagtcgg gcgcaggcgc ctcctccgca gcccgctcca   1020 

tggtcggcgc ccacagcccg cggcggcctg tcttgcgctc cacttccttc acatcctcct   1080 

ccgcctcctc gttttcaggc gccgccggcg gcgctgtgtg gaggcccgcg agctgaaatt   1140 

cgcggtgcga cgggagggag tggagaagga ggtgaggggg cccaggatcg cggggcgccc   1200 

tgaggcaagg ggacgccggc gggccgaagc gcagcccgcc gcccgcaggc tcggctccgc   1260 

cactgccgcc ctcccggtct cctcgcctcg gccgccgagg cagggagaga atgagccccg   1320 

ggacccgccg ggggacggcc cgggccaggc ccgggatcta gacggccgta gggggaaggg   1380 

agccgccctc cccacggcgc cttttcggaa ctgccgtgga ctcgaggacg ctggtcgccg   1440 

gcctcctagg gctgtgctgt tttgttttga ccctcgcatt gtgcagaatt aaagtgcagt   1500 

aaa atg tcc act agg acc cca ttg cca acg gtg aat gaa cga gac act     1548 
    Met Ser Thr Arg Thr Pro Leu Pro Thr Val Asn Glu Arg Asp Thr 
      1               5                  10                  15 

gaa aac cac acg tca cat gga gat ggg cgt caa gaa gtt acc tct cgt     1596 
Glu Asn His Thr Ser His Gly Asp Gly Arg Gln Glu Val Thr Ser Arg 
                 20                  25                  30 

acc agc cgc tca gga gct cgg tgt aga aac tct ata gcc tcc tgt gca     1644 
Thr Ser Arg Ser Gly Ala Arg Cys Arg Asn Ser Ile Ala Ser Cys Ala 
             35                  40                  45 

gat gaa caa cct cac atc gga aac tac aga ctg ttg aaa aca atc ggc     1692 
Asp Glu Gln Pro His Ile Gly Asn Tyr Arg Leu Leu Lys Thr Ile Gly 
         50                  55                  60 

aag ggg aat ttt gca aaa gta aaa ttg gca aga cat atc ctt aca ggc     1740 
Lys Gly Asn Phe Ala Lys Val Lys Leu Ala Arg His Ile Leu Thr Gly 
     65                  70                  75 

aga gag gtt gca ata aaa ata att gac aaa act cag ttg aat cca aca     1788 
Arg Glu Val Ala Ile Lys Ile Ile Asp Lys Thr Gln Leu Asn Pro Thr 
 80                  85                  90                  95 

agt cta caa aag ctc ttc aga gaa gta aga ata atg aag att tta aat     1836 
Ser Leu Gln Lys Leu Phe Arg Glu Val Arg Ile Met Lys Ile Leu Asn 
                100                 105                 110 

cat ccc aat ata gtg aag tta ttc gaa gtc att gaa act gaa aaa aca     1884 
His Pro Asn Ile Val Lys Leu Phe Glu Val Ile Glu Thr Glu Lys Thr 
            115                 120                 125 

ctc tac cta atc atg gaa tat gca agt gga ggt gaa gta ttt gac tat     1932 
Leu Tyr Leu Ile Met Glu Tyr Ala Ser Gly Gly Glu Val Phe Asp Tyr 
        130                 135                 140 

ttg gtt gca cat ggc aag atg aag gaa aaa gaa gca aga tct aaa ttt     1980 
Leu Val Ala His Gly Lys Met Lys Glu Lys Glu Ala Arg Ser Lys Phe 
    145                 150                 155 

aga cag ggt tgt caa gct gga cag act att aaa gtt caa gtc tcc ttt     2028 
Arg Gln Gly Cys Gln Ala Gly Gln Thr Ile Lys Val Gln Val Ser Phe 
160                 165                 170                 175 

gat ttg ctt agt ctg atg ttt aca ttt att gtg tct gca gtt caa tac     2076 
Asp Leu Leu Ser Leu Met Phe Thr Phe Ile Val Ser Ala Val Gln Tyr 
                180                 185                 190 

tgc cat cag aaa cgg atc gta cat cga gac ctc aag gct gaa aat cta     2124 
Cys His Gln Lys Arg Ile Val His Arg Asp Leu Lys Ala Glu Asn Leu 
            195                 200                 205 

ttg tta gat gcc gat atg aac att aaa ata gca gat ttc ggt ttt agc     2172 
Leu Leu Asp Ala Asp Met Asn Ile Lys Ile Ala Asp Phe Gly Phe Ser 
        210                 215                 220 

aat gaa ttt act gtt ggc ggt aaa ctc gac acg ttt tgt ggc agt cct     2220 
Asn Glu Phe Thr Val Gly Gly Lys Leu Asp Thr Phe Cys Gly Ser Pro 
    225                 230                 235 

cca tac gca gca cct gag ctc ttc cag ggc aag aaa tat gac ggg cca     2268 
Pro Tyr Ala Ala Pro Glu Leu Phe Gln Gly Lys Lys Tyr Asp Gly Pro 
240                 245                 250                 255 

gaa gtg gat gtg tgg agt ctg ggg gtc att tta tac aca cta gtc agt     2316 
Glu Val Asp Val Trp Ser Leu Gly Val Ile Leu Tyr Thr Leu Val Ser 
                260                 265                 270 

ggc tca ctt ccc ttt gat ggg caa aac cta aag gaa ctg aga gag aga     2364 
Gly Ser Leu Pro Phe Asp Gly Gln Asn Leu Lys Glu Leu Arg Glu Arg 
            275                 280                 285 

gta tta aga ggg aaa tac aga att ccc ttc tac atg tct aca gac tgt     2412 
Val Leu Arg Gly Lys Tyr Arg Ile Pro Phe Tyr Met Ser Thr Asp Cys 
        290                 295                 300 

gaa aac ctt ctc aaa cgt ttc ctg gtg cta aat cca att aaa cgc ggc     2460 
Glu Asn Leu Leu Lys Arg Phe Leu Val Leu Asn Pro Ile Lys Arg Gly 
    305                 310                 315 

act cta gag caa atc atg aag gac agg tgg atc aat gca ggg cat gaa     2508 
Thr Leu Glu Gln Ile Met Lys Asp Arg Trp Ile Asn Ala Gly His Glu 
320                 325                 330                 335 

gaa gat gaa ctc aaa cca ttt gtt gaa cca gag cta gac atc tca gac     2556 
Glu Asp Glu Leu Lys Pro Phe Val Glu Pro Glu Leu Asp Ile Ser Asp 
                340                 345                 350 

caa aaa aga ata gat att atg gtg gga atg gga tat tca caa gaa gaa     2604 
Gln Lys Arg Ile Asp Ile Met Val Gly Met Gly Tyr Ser Gln Glu Glu 
            355                 360                 365 

att caa gaa tct ctt agt aag atg aaa tac gat gaa atc aca gct aca     2652 
Ile Gln Glu Ser Leu Ser Lys Met Lys Tyr Asp Glu Ile Thr Ala Thr 
        370                 375                 380 

tat ttg tta ttg ggg aga aaa tct tca gag ctg gat gct agt gat tcc     2700 
Tyr Leu Leu Leu Gly Arg Lys Ser Ser Glu Leu Asp Ala Ser Asp Ser 
    385                 390                 395 

agt tct agc agc aat ctt tca ctt gct aag gtt agg ccg agc agt gat     2748 
Ser Ser Ser Ser Asn Leu Ser Leu Ala Lys Val Arg Pro Ser Ser Asp 
400                 405                 410                 415 

ctc aac aac agt act ggc cag tct cct cac cac aaa gtg cag aga agt     2796 
Leu Asn Asn Ser Thr Gly Gln Ser Pro His His Lys Val Gln Arg Ser 
                420                 425                 430 

gtt tct tca agc caa aag caa aga cgc tac agt gac cat gct gga cca     2844 
Val Ser Ser Ser Gln Lys Gln Arg Arg Tyr Ser Asp His Ala Gly Pro 
            435                 440                 445 

gct att cct tct gtt gtg gcg tat ccg aaa agg agt cag aca agc act     2892 
Ala Ile Pro Ser Val Val Ala Tyr Pro Lys Arg Ser Gln Thr Ser Thr 
        450                 455                 460 

gca gat ggt gac ctc aaa gaa gat gga att tcc tcc cgg aaa tca agt     2940 
Ala Asp Gly Asp Leu Lys Glu Asp Gly Ile Ser Ser Arg Lys Ser Ser 
    465                 470                 475 

ggc agt gct gtt gga gga aag gga att gct cca gcc agt ccc atg ctt     2988 
Gly Ser Ala Val Gly Gly Lys Gly Ile Ala Pro Ala Ser Pro Met Leu 
480                 485                 490                 495 

ggg aat gca agt aat cct aat aag gcg gat att cct gaa cgc aag aaa     3036 
Gly Asn Ala Ser Asn Pro Asn Lys Ala Asp Ile Pro Glu Arg Lys Lys 
                500                 505                 510 

agc tcc act gtc cct agt agt aac aca gca tct ggt gga atg aca cga     3084 
Ser Ser Thr Val Pro Ser Ser Asn Thr Ala Ser Gly Gly Met Thr Arg 
            515                 520                 525 

cga aat act tat gtt tgc agt gag aga act aca gct gat aga cac tca     3132 
Arg Asn Thr Tyr Val Cys Ser Glu Arg Thr Thr Ala Asp Arg His Ser 
        530                 535                 540 

gtg att cag aat ggc aaa gaa aac agc act att cct gat cag aga act     3180 
Val Ile Gln Asn Gly Lys Glu Asn Ser Thr Ile Pro Asp Gln Arg Thr 
    545                 550                 555 

cca gtt gct tca aca cac agt atc agt agt gca gcc acc cca gat cga     3228 
Pro Val Ala Ser Thr His Ser Ile Ser Ser Ala Ala Thr Pro Asp Arg 
560                 565                 570                 575 

atc cgc ttc cca aga ggc act gcc agt cgt agc act ttc cac ggc cag     3276 
Ile Arg Phe Pro Arg Gly Thr Ala Ser Arg Ser Thr Phe His Gly Gln 
                580                 585                 590 

ccc cgg gaa cgg cga acc gca aca tat aat ggc cct cct gcc tct ccc     3324 
Pro Arg Glu Arg Arg Thr Ala Thr Tyr Asn Gly Pro Pro Ala Ser Pro 
            595                 600                 605 

agc ctg tcc cat gaa gcc aca cca ttg tcc cag act cga agc cga ggc     3372 
Ser Leu Ser His Glu Ala Thr Pro Leu Ser Gln Thr Arg Ser Arg Gly 
        610                 615                 620 

tcc act aat ctc ttt agt aaa tta act tca aaa ctc aca agg agt cgc     3420 
Ser Thr Asn Leu Phe Ser Lys Leu Thr Ser Lys Leu Thr Arg Ser Arg 
    625                 630                 635 

aat gta tct gct gag caa aaa gat gaa aac aaa gaa gca aag cct cga     3468 
Asn Val Ser Ala Glu Gln Lys Asp Glu Asn Lys Glu Ala Lys Pro Arg 
640                 645                 650                 655 

tcc cta cgc ttc acc tgg agc atg aaa acc act agt tca atg gat ccc     3516 
Ser Leu Arg Phe Thr Trp Ser Met Lys Thr Thr Ser Ser Met Asp Pro 
                660                 665                 670 

ggg gac atg atg cgg gaa atc cgc aaa gtg ttg gac gcc aat aac tgc     3564 
Gly Asp Met Met Arg Glu Ile Arg Lys Val Leu Asp Ala Asn Asn Cys 
            675                 680                 685 

gac tat gag cag agg gag cgc ttc ttg ctc ttc tgc gtc cac gga gat     3612 
Asp Tyr Glu Gln Arg Glu Arg Phe Leu Leu Phe Cys Val His Gly Asp 
        690                 695                 700 

ggg cac gcg gag aac ctc gtg cag tgg gaa atg gaa gtg tgc aag ctg     3660 
Gly His Ala Glu Asn Leu Val Gln Trp Glu Met Glu Val Cys Lys Leu 
    705                 710                 715 

cca aga ctg tct ctg aac ggg gtc cgg ttt aag cgg ata tcg ggg aca     3708 
Pro Arg Leu Ser Leu Asn Gly Val Arg Phe Lys Arg Ile Ser Gly Thr 
720                 725                 730                 735 

tcc ata gcc ttc aaa aat att gct tcc aaa att gcc aat gag cta aag     3756 
Ser Ile Ala Phe Lys Asn Ile Ala Ser Lys Ile Ala Asn Glu Leu Lys 
                740                 745                 750 

ctg taa cccagtgatt atgatgtaaa ttaagtagca agtaaagtgt tttcctgaac      3812 

actgatggaa atgtatagaa taatatttag gcaataacgt ctgcatcttc taaatcatga   3872 

aattaaagtc tgaggacgag agc                                           3895 

 
           
             13  
             506  
             DNA  
             H. sapiens  
             
 
           
            13 

ggaggtttgt gtcgtgtttg gttaactaaa cctaaaggtg acttactcgt tttctttcct     60 

ctgtacctct ccaaaggaac tgagagagag agtattaaga gggaaataca gaattccctt    120 

ctacatgtct acagactgtg aaaaccttct caaacgtttc ctggtgctaa atccaattaa    180 

acgcggcact ctagaggtaa tcatgtaggt ggaaacaagc agtaactttg gagagtcttt    240 

agagtgacct tagatcttgg cttgatttgt atgccatact ggatatatcc tgcggctttt    300 

taagcaagaa tggaaacatt aaaaaatatt tttggagttt atgctttgaa cgatagtcaa    360 

tgaaatgttg aaaataaatt ttggtaaata ttacggttat cagaatattt cattttactc    420 

tgctaatgaa cagtttacct tttttagcaa atcatgaagg acaggtggat caatgcaggg    480 

catgaagaag atgaactcaa accatt                                         506 

 
           
             14  
             506  
             DNA  
             H. sapiens  
             
 
           
            14 

ggaggtttgt gtcgtgtttg gttaactaaa cctaaaggtg acttactcgt tttctttcct     60 

ctgtacctct ccaaaggaac tgagagagag agtattaaga gggaaataca gaattccctt    120 

ctacatgtct acagactgtg aaaaccttct caaacgtttc ctggtgctaa atccaattaa    180 

acgcggcact ctagaggtaa tcatgtaggt ggaaacaagc agtaactttg gagagtcttt    240 

agagtgacct tagatcttgg cttgatttgt atgccatact ggatatatcc tgcggctttt    300 

taagcaagaa tggaaacatt aaaaaatatt tttggagttt atgctttgaa cgatagtcaa    360 

tgaaatgttg aaaataaatt ttggtaaata ttacggttat cagaatattt cattttactc    420 

tgctaatgaa cagtttacct tttttagcaa atcatgaagg acaggtggat caatgcaggg    480 

catgaagaag atgaactcaa accatt                                         506 

 
           
             15  
             119501  
             DNA  
             Homo sapiens  
             
 
           
            15 

ggcgcctgct gccctcaggg tccgcgccca gcccgcagct gctcagatcc ggagacggga     60 

aggtttgttg gcgagaacct gactcccggg tcacagttaa ggatgcaaga gcccggcgcc    120 

ttcccgtagc cccggccctg tcattaatta atgctggggc tccattcggt gcagcgcagt    180 

cccagggatg caaccgcaac ttttgcgcac aataggctct cgatctgtaa tccagccaac    240 

ccaggcctgt agtgtgtaaa tgccaactca gcgggagggc tctggctgtc gcccagagcc    300 

gtttctcggc tctttcgcgg ttgccggcgc gctcgggaca ggaggaaccc gcagcccgcg    360 

ggagtcagcg gagacccgac cagcactatc cagccctctg caccgccccc gcggcgaggt    420 

ctggaccaag tcgcccctag caacaacagc cgggccggct ttctcaggcc atgctgattg    480 

gcgggactcc gggtggcggc ctgtcgtcac ttccggcagc cggaggcagc agaggaagcc    540 

gaggggcggc catcttggct ccgtgaggct ctgaggtgcc ggggtgcggc ggcggcagcg    600 

gcggccagca gggcggaggc tgaggcagca agctcgctag agagggagaa gcagtcgggc    660 

gcaggcgcct cctccgcagc ccgctccatg gtcggcgccc acagcccgcg gcggcctgtc    720 

ttgcgctcca cttccttcac atcctcctcc gcctcctcgt tttcaggcgc cgccggcggc    780 

gctgtgtgga ggcccgcgag ctgaaattcg cggtgcgacg ggagggagtg gagaaggagg    840 

tgagggggcc caggatcgcg gggcgccctg aggcaagggg acgccggcgg gccgaagcgc    900 

agcccgccgc ccgcaggctc ggctccgcca ctgccgccct cccggtctcc tcgcctcggc    960 

cgccgaggca gggagagaat gagccccggg acccgccggg ggacggcccg ggccaggccc   1020 

gggatctaga cggccgtagg gggaagggag ccgccctccc cacggcgcct tttcggaact   1080 

gccgtggact cgaggacgct ggtcgccggc ctcctagggc tgtgctgttt tgttttgacc   1140 

ctcgcattgt gcagaattaa agtgcagtaa aatgtccact aggaccccat tgccaacggt   1200 

gaatgaacga gacactgaaa acgtaagtaa cctgggcgtt gtagttggcg gaccttcggg   1260 

gtggcattcg tgctcctcgg gcagtgcctt gcagtcgggt gttcccccca gccgaacgct   1320 

ctggaaatag agggcaggcc gtagtcaccc aggaggcagc caggtcggac cgtttcctcc   1380 

agaagtctgc cgtgtcccgc tgttcgcggg cgggtctgcg aagtacatcg attatgccgg   1440 

cagtctagtc ggttaataaa gcccaggagt tgcagcgtta cggatcggtg ctttgagagg   1500 

ccaggttgcc gcgcaatgga ttgtgcaaac gtgtgtgtca gatcactgca gtggtcagtg   1560 

cttattttag ccgaactctg cttttaactt ggtcaggcag ttcttgagag actgtcacat   1620 

taataacata tgttaccggt gctgattaag agtaatcgat tgggtcaagt gggcggtctc   1680 

gttctttaag atggtctgga actaaattta atcacagtca ctaagtgtcc actgagggat   1740 

ctttgcggtc cccttaggaa ttccaaaaca ctagcgcgca gcctttatta aggcagtttc   1800 

ctttccatac aaatcttttt tgaaggagtt ggttaaacat tttgaaaagc agatgtatag   1860 

tgaagctctg ctctgccact cactgcctag ctgagggaca cccgctgggg gcttcgctgt   1920 

cctccttcct aaaaagagat tggcttagat gagctcttag gtccctttca gcgctcacag   1980 

gctatggttt tataaaagga acctttgatt ttgttcatgt gaaactacaa aatgccagga   2040 

acagcattgc tagagaatga gaacttgtag tagaaattcc attgaagaaa cgtttgactc   2100 

tgttcgtttt ctaactctgt tctcctctaa cactgggttc aaaagtgttt caatctagtt   2160 

gttgactata ttctgtaaaa catctagtaa ataatttgta aagaaacttc actggccttt   2220 

cattaaaagt gttatgaggt aattgctggc acgaaatgtc ttctcttagg gaatgcttcc   2280 

ttgctttgag tgttttcatg ctttcagtaa tgtcctgaga tgttgtggcc tagtggagtt   2340 

aatgctttca ttttgatctt caaaaatgcc gcttgtttgc tggatagctg tttgataatt   2400 

taatccgtaa acgtaaacca tagcctaaag catccctgta gcatattagt atacaatatt   2460 

taatgctctg tggccctgag taagtagaac agtgatgtac ctttctccac ctgagataga   2520 

ttagaaaatt atataaagag tgagtaatag aaactcttag actaggtgag tcagggaact   2580 

aatttcctta tagtcctttt aaagaaacct tatttatttg tttatttatt tatttattta   2640 

cttatttatt ttttgagaca gaccgagact gtctcccagg ctggagtgca gtggtgcgat   2700 

cttggctcac tgcagcctcc acctcccagg ctgaagtgat tatcatgcct cagcctcccg   2760 

agtagctggg attactggcg tgcaccacca cgcccggcta atttttgtat ttttagtaga   2820 

gacagggttt caccatgttg gccaggctgg tctagaactc ctggcctcat gtgatccacc   2880 

cgcctcggct ccccaaagtg ctgagattac aggcatgagc cagtgtgccc aactgattag   2940 

ttttgatcat tgatcttcac tcagagaagc aaaaccttac attgaaccag agtaggagct   3000 

ccatgctttc taaactgaag ccaaaaacag tcatagcaga tttgtgataa tgaaggattt   3060 

caaatgggtc ttttttcttt ctttcttttt tgagatggag tctggctctg tctcccaggc   3120 

tggagtgccg tggcatgatc tcggctcact gcaacctccg cctcccgggt tcaagtgatt   3180 

ctcctgcctc agcctcctga gtagccagga ttacaggcat gtgccaccac tcccggctaa   3240 

ttttgtattt ttagtagaga cggggtttct ccatgttggt cgtgctggtc tcaaactccc   3300 

gacttcaggt gatcctcccg cgtcagcctc ccaaagtgct gggattacag gcgtgagcca   3360 

ccacgcccag ccatgtagtg tatttaaaat gaatttttga ctttttttaa aaatcaagtt   3420 

tatcacacat cgttgcatta atttaccatg ccctgttaca tttttaactc ttgcattggc   3480 

atgttctgga aggagctgtg tagctttcac agtgtggagc ccttgtgtca gtgttataac   3540 

tcaggtatag tccatattaa ttacctacat tactgcactg ctaagtatta gacttcctgc   3600 

caattgagtg gtgaatgtac aagaatgaat gggagctctc attctgttga gaaccttttt   3660 

tcttaaagtt aggtttgttg agatgtaatg ttcatctgtt ttaagtatac agtttggtga   3720 

attttgacaa gcgtatagtt atgtaaccgc tatcacaatc aagatgtaga acacttccat   3780 

tgccagaaag gtcccttatg gccctgtata gtcagtgccc tctccctttc ttagcccctg   3840 

ggtaaccact gatctgcttt ctgtccctgt agttttgcct tttctaggat gctatgtaaa   3900 

tggagtcaca gtgtaaataa tcttttgtgt cttctttcac ttagagtagt gcttttgaga   3960 

tttatttgaa tgtgtatcag tatcagtagt tcattccttt ttattgctga gtaagtattt   4020 

ccttgtttgg atgtgccaca atttttttta atccactcac cagtgatgga catttttggc   4080 

tattgtgact agaacagttt tcttttagta ttctgtaaaa atacttttta ttgtgcttac   4140 

cccaggaatc ttatttaaat tttaagtaat tgtatataac tgtgataaga atgtcgctta   4200 

ttagatcaag actaagaaaa ggcaggccgg gtgtggtggc tcatacctgt aatcccagca   4260 

ctttgagagg ctgaggctgg cggatcacga ggtcaggaga tcgagaccat cctggctaac   4320 

atggtgaaac cctgtctcta ctaaaaatac gaaaaattag ccgggcgtgg tggcaggcac   4380 

ctgtagtcct agctactcgg gaggctgagg caggagaatg gcatgaacct gggaggcaga   4440 

gcttgcagtg agccgagatt gggccaccac attccagcct gggcgacaga gccagactcc   4500 

atctcaaaaa aaaaaaaaaa ttagccaggt gcggtggtgc atgcctgtaa ttccagctac   4560 

tcaggaggct gacgtgggag aatcacttga acacaagagg tgaaggttgc agtgagccga   4620 

tatcatgcca ctgcactgca gcctgagtga cagagtaaga ctctgtctcc aaaaaaaaaa   4680 

aaaaaaaaaa gcagacaact tgcaacatta tcttcatcct tgtacactaa tttgtttttg   4740 

tttgtttgat ttccaaatat taatgtccac ccttagtgaa tgggtatata aaagtttact   4800 

gttggccagg tgcagtggct cacgcctgta atcccagcac tttgggaggc cggggcaggt   4860 

ggatcacctg aggtcaggag ttcgagacca gcctgaccaa gatggcaaaa ccctgtctct   4920 

actaaaaata caaaaattag ccgggtgcgg tggcgggcac ctgtaatccc agctacttgg   4980 

gaggctgagg ctggagaatc gcttgaaccc tggagacgga gagtgcagtg agctgagatc   5040 

aagccattgc cctccagcct gggcgacaga gggatactcc gtctcaaaaa aaaaaaaaaa   5100 

aaaaaaaagg ccgggcgcgg tggctcacac ctgtaatccc agcactctgg gaggccgagg   5160 

cgggcagatc acgaggtcag gagatcgaga ccatcctggc taacacggtg aaaccctgtg   5220 

tctaccaaaa atataaaaaa ttagccgggc gtggtggcag gtgcctgtag tcccagctac   5280 

tcgggaggct gaggcaggag aatggcgtga tcccgggagg cggagcttgc agtgagccaa   5340 

gatggcgcca ctgcactcca gcctgggcga cagagtgaga ctccatctca aaaaaaaagt   5400 

tcactgttgc tgcatcgtgt tatagctcaa aagaactact caatctgatc cagtgaggtt   5460 

gctgagactc agagaggtga caaaggctgc tagtaatgac agaagaccac taactattta   5520 

gtagcaaagc ctctactggg ccccagatct ctagcttagg ctccacaagg agatgtagtt   5580 

gtacctgtac atagagtatt tctaaaactt ttttttaagc ttgtagatca ggggtgtcca   5640 

atcttttggc ttccccgggc cacattggaa gaattgtctt gggccacaga taaaatacac   5700 

taacactaac aatagctgat aagctttaaa aaaactgcaa aaaaaatctc acagtgtttt   5760 

aacaaagttt atgaatttgt gttgggtcac tttcaaagct gtggtgggct gcatgcagcc   5820 

ctagggctgt gggttggaca agcttgctgt agattttatt ttgattttga gacagtatct   5880 

cgctctgtca cccaggctgg agtgcagtgg agcaatcaca gcttgctgta accttgacct   5940 

cttgggctca agcaatcctt ccgactcagc ctcctgagta gctgggacta caggcgtgcc   6000 

ccaccacatg catggctaat ttttaatttt ttcgtagaga tgagatctcc ctgtattgcc   6060 

caaggtggtc tctaactcct gggctcaagc aggcctcctg tcccagcctc ccaaagcact   6120 

ggaattacag gtgtgagcca ccacactcag tcaaaactat tttttaaaat attttattat   6180 

aggaaaattt aaaaaaatag aatgttattt atcaatgctt ctcagccaca gggtgatttt   6240 

gccctctagt ggacatttga caatgtctaa agacatcttt ggttatcaca gctggagaaa   6300 

ggtttggctg accaggaatg ctactaaaca ttttacagta cgtaggacag ccttccacag   6360 

caaagaatta cccggcctaa aatgtcagta gtgccagcgt tgagaaaccc tggtatgtac   6420 

ttagcccccc atgtactcaa cagcgcagct cagtggccaa tcttatttca tttataaatg   6480 

aagaagcaaa tgcagtatca tttcctctct aaagctttta gaagagataa agcctgtttt   6540 

aagaaaaaag caatactttt atcatatttt cttaatatca aatatgcagt atttaaattt   6600 

tctcacattt ctaattttta aactgttcaa attagaatcc agcttgaatt catacattat   6660 

agttggctga tatgtcaaat atgctttttt ttttttttta attgagatgg agtcttgctc   6720 

tgtcgcccag gttggagtgc agtggtgcaa tctcggctca ctgccaacct ctgccgcccg   6780 

ggttcaagcg attgtcgtgc gcagcctccc gagtagctgg gattacaggc tcccgccacc   6840 

atgcctggct attttttttt tttttttttt ttttttttta gtagagatgg ggtttcgcca   6900 

tgttggccag gctgttctca aactcctgac ctcaggtgat ccgcccgcct tggcctccca   6960 

aagtgctggg attacaggcg tgagccactg tacctggtca aaatatgctt tttaaaggca   7020 

accaaacagt ttgcatttca gtttatgttc tatagttata tggagccacg gatacatcct   7080 

ttttctatac tggcaaaatg agaaacatat ttttcacctg aatttcaaag gatatgacac   7140 

ttcgtaagcc tggtaatgtt attggccaaa gtaccagagg cccagggctt tcccagttat   7200 

ttaacagtta ctgatatgtg tgcatcatgt acttattatt agttaatgca aatagtcccc   7260 

caaatttctg acctctgtga aactgatgat gctgttgtct agtcagtcat cggttatgtg   7320 

agactgaatt aacctattca gcaagtgtga atgcctaccg tgtgtatgat actgtgctag   7380 

gtgctgtaga ggccatatac ctgggacaca tagctttcct gctctttagg atttcctgct   7440 

ccttgcagga caaagcagcc tgagctttat gaaactagtc tgtaactctc aaacttaagc   7500 

aaacattaga atcacctgaa gggctttaga accgtgatca ctgggcccta cccctagacc   7560 

ttgattttac ccgtagaatt ggaatttcta acaagttgcc aggtgatgtt gatgctccag   7620 

gtccggggac cactcttaag aatcactata gcaggaattt ctgatgttta tttattaaga   7680 

aaaaaaaatc actgccttag tgtgcagtga aggcttgcta actaaactat actcctttta   7740 

gattgtactg tgactatcaa aggaagattt ccagaccatt taattgagtt ttcaggttcc   7800 

atgagtttaa aaaaaactgt ttattaaaaa ttgtggttct ggaaaataac aatagttgcc   7860 

atttggtgat cacttaactg tataccagcc agcaatactt tgtagagtat ctcatttaaa   7920 

atatgtaata tggttttatt taattagctt tttttttttt taaatttcct gaggcggagt   7980 

ctcacactgt tacctgggct ggagtgcagt ggcacgatct cgctcgctgc aacctccgcc   8040 

tcccgggttc aagcgattct cctgcctcag cctcccaggt agctaggatt acaggcagcc   8100 

gccaccacac ccagctaatt tttaaatttt attttatttt ttgagacaga gtttcactct   8160 

tgttgcccgg gctggagtgc agtggcatga tcttggctca ctgcaacctc cgcctcctgg   8220 

cttcaagcaa ttctgcctca gcctcccgag tagctgggat tacaggtgcc tgttaccatg   8280 

cccagctgat ttttttgtat tttcggtaga gactgggttt caccatgttg gcaggctgat   8340 

ctggaactcc tgacctcatg atcctcccac ttccctcctc ggcctcccaa agtgctggaa   8400 

ttacaggcgt gagccactgt gccccggctt aatcagcttg tcaacttcta agcacaacct   8460 

gttgaatcaa gctgtttggg ccttatcaga aaaaagttgg cctatagttt cagctactca   8520 

ggaggctaag gccagaggat cacttgaggc caggagttcc agtcgacctg gacaacatgg   8580 

tgaaactatg tatcttaaga aagaaaaaaa aaagttgatc tctgaagaat tcatgaaaat   8640 

atttagtcag ttttcaggga aagatcttat agacttcaat ttgagcatcc ttatcttatg   8700 

tatgtaaatg aggtaaaggt tgaaatttgc agtaaataga attttggtca tttaagttat   8760 

gtagctcatg atatatacat tgtataacta tttagactta catggtgcat gatttacatt   8820 

gtaattacat agaggcttat acagtctaat aaaaattaat attaactatt tgattgcaaa   8880 

gaggattgtt ctgcatttta ttactttttt tttttttttg agacagagtt tcactcttgt   8940 

tgccaggctg gagtgcaatc tcgtgacctt ggctcactgc aacctccgcc tgccagccta   9000 

agtagctggg gttacaggca cacaccacca tgcccagcta attttttgta tttttagtag   9060 

ggatggggtt tcaccatgtt agccaggctg gtctcaaact cctcaccttg ggttatccgc   9120 

ctgccttggc ctcccaaagt gctgggatta caggcttgag ccactgcgct cggcctgcat   9180 

tttattattc taagatatag ccaaatttta tgcctggaat tttttcctgg gctggaacaa   9240 

attcctagta agagtcaggg aatattccgt gacttgtggc tttggttaaa aaagaaaaag   9300 

gagtcaggga atgcagtacc ctctgatcac cactgggagg actaaagcag aaaattcatt   9360 

tgtctcatat ccattttcaa atttcaaatt aaacatgaag gagaaaataa atctcttacc   9420 

tgggaagctt taatgtcctg tctcacacaa gaagttaaag gttgtgcttg gagttggtct   9480 

gcaaaagtaa taaggaattt gtactcaccc gtctgcacct gcttgtacag aacaattgga   9540 

agggcagaag ttggctttga aagaaaaggc ctttttttgg aggtgggagg ggcatccaat   9600 

tttgtcttca gccgagagtt cgctagcact acactctagc cactcaagct gctcaactat   9660 

ggttggtctt gtgtacttct gtgtgcacta gataagacat tgtttctgtg ggttatgtgg   9720 

gaccttgaag ttcagtgttg aagctcaaac aaagcaggtg ttttttctgt atttcttgtt   9780 

gacaggcatt tgctttttgt tggacctaaa tattgtgggg tttgtgtatg gacatttgac   9840 

acaaaaatct gtattggtag aatttaatat aaaatcagag aagttgaatt cacaggtttt   9900 

gttcatagaa ttttacataa ctctagtctt ttttcttttt ttgtgatgga gtcttgctct   9960 

gttgcccagg ctggagtgca gtggcatgat cttggctcac tgcaacctct gcctcctggg  10020 

ttcaagtgat tgtcctgcct cagcctcccg agtagctggg attacaggca cccgccacca  10080 

cgcctggcta atttttgtat ttttagtaga aacggggttt caccatggcc aggctggtct  10140 

tgaactcctg acctcaagtg atccacctgc ctcggcctcc caaagtgcta ggattatagg  10200 

catgagccac agcgcctggc cacaatctta cactactttc ctgaagggat gtgtgatgga  10260 

aagagtctgg gcttgaaagt ggaagacaaa aatgagagtc taagactgat cgagataaag  10320 

attctgaaga ggtagaatgg acctcataag atggagcaaa aaagaaggaa caacatataa  10380 

aaggagaaat tagaatttag agttatagac tggaatttga aactagtctt gagatttaac  10440 

tgtggacaaa ttcactcggc tgtgcctcat ggtttttttt tttttaaatc aaaagagaat  10500 

aacatcattc aagttgtgtc ttggtttttt tgtttgttta cttagatttt tatgacttca  10560 

ctttctcaat ttcctctgtg gccagattca tcaggcattc agtcactttc atctctgtca  10620 

ggctggcctt gtgttctgtc tgtctgttct gctgcatagt tgtcatcctg agatctccct  10680 

tcacccatat cctagggatt ccctttgcct ttcctgttcg atccattttc ttccccttgg  10740 

ttcactccca ggtttcattg cagcagttcc tccagtgatt ttctgagaaa gttgctcaga  10800 

ggtaaatttt taaaatcctt tcatatctgc aaacatcttt attctgttct catacttgat  10860 

tgatattttg gctgcatata gaattctaga ctgaatgccc tttttcctca gaattttgtt  10920 

ttctgtctta tatagcatct gacactccga tttggagaga gagaatgcta ttttgagtct  10980 

tgcttatttt tctgtttgtt taaggctgat tggaagtttt gtgcatttgg atggatcttg  11040 

aatacaacag tgggacacac tgttatttct ttgtggtgct cttgatacca atatatttag  11100 

tcttatcact tggcctaggc aagcacggaa tgcccatgtt ccagggagct gagtcgggag  11160 

agggcagaag gaaagatctg tggctttctg ctttctctgc ttgttttcag tgtccctgcc  11220 

ctcagttgtg ccctgtgtcc ccaagcccag agactttcca ttttgccctt tctaaagaac  11280 

ctccagtttt ttgcctgagt gggagaggag acccgggggt ctgttattta acagactgat  11340 

agatcttctt gtttcaggct tacttcactc acacttctag aggtacttgt actaccagtt  11400 

cctgaacctt ttgagagttc tataatacaa atcaggattt tccaatatct ccatagctgg  11460 

cttaggatta atctttctta tatgtgttaa gtcattttcc ttcttttttt agtttctgaa  11520 

agtatatctg ttaccacttt tattttcttt gtcttgtggc ttttttcctt atgccttata  11580 

tttttttcct ttactttcat attaatggag tttggagagg gaggggaagt aaatgcagcc  11640 

atgatttata accagacttg gattaggtgt ttacatatgt caatacatgt ctttaaaatt  11700 

tagctagtac ttgttattat aaataacaaa ctaagattga taggcttctt gaaaaattgg  11760 

cggtaaattt ggctaatggt gggttgttgt agtagagtag cgtttcccct tttcacccaa  11820 

gctttgttac ctcttcttgg gtggtgcctg gcctgagatg tccttcatct ctcataagaa  11880 

ctctcctact tgccctttga ggactccatc ccttcacatc ttggggtacc ttttttcctt  11940 

catctcaccc aaatgtgatc atgtcctttg ggtgcctaga gctgcattat ccagcacagt  12000 

agcaactagc cacatgtggg gctaccaagc acttgaaacg tggttagttt gaatttaggt  12060 

gttctgtaag tataaaagat aaaccagttc aaagacagta tttcaaaaat aggatataaa  12120 

gcctttttat attatgcatt gaaatattgg ggggtatatt gagttaaata aaatggtatt  12180 

taatttaacg tattaaatat gtttcttttt acatttttta atggagctac tagaaaattg  12240 

aaaattacat atgtatgtca cattatacac ctattggaca gcattagagt attcactctg  12300 

attttctctt ggggcaggaa ttgccccttg tttcagttgc tattcccccg ttagcacccc  12360 

gtgtatatca tgagtgcctt gaaggtttga caccacactt ttctgtttct tttattccct  12420 

gctaatgcct accatatagt tgactagccg aaagttactg aataaacatt tttttttttt  12480 

ttttttgaga tgaagtctca ctctgtcacc cagactggag tgcagtggtg cgatctcggc  12540 

tcaccgcaac ctccgcctcc caggttcaaa cgattctcct gcctcagcct tctgagtagc  12600 

tgggactaca ggcacccgcc accatgcctg gctaattttt ttatttttag tagagatggg  12660 

gtttcaccat attggccagg ctggtctcga actcctgacc ttgtgatcct cctgcctcag  12720 

cctcctaaag tgctgggatt acaggcgtga gctaccgcac ctggcctgaa tcaagatttt  12780 

tttagccaca acttgtgcct tacaagtttt ttattctaag gattagacaa gtaaattatt  12840 

tttcaccgta ttacattagt tcacctacta taccagtaac aattatttta ttcaaaagtg  12900 

aaacagattt tactatattt atgggacaat aacagttccc ccttcctatt catattctta  12960 

gatgctttct cataaattca gctgtgaaga gtcacattat ctttgatcca tgtgagacta  13020 

tcttcttgtt ttatctactc ctgttagtct ccatatgtca ttactcttac cctccacccc  13080 

acgttactgt tttaatgtgt ttagtatgtg tatgtgttct tacatagttt attttggtat  13140 

gtttggtact ttatgtaaat attacatatg tcttatctgt gcgcttaata tattgcatct  13200 

aactgctgaa tagcagtgag atgtatgcat ctaccacatt ttaccagtct gctcgccaga  13260 

ggtgcacatg ttaattttct ccaactctgt caccacaaaa aaaatgcttc aacatcttca  13320 

tgcatgtccc cttatggagc aatgtaagag tttctttggg atatatagct tggaatggac  13380 

ttgatgggtc acaggaaatg tcagattgtt cttctagatg gctgcttcca tcaatagtgc  13440 

accacagttt ttgtattccc gtttctctgc caacatttca gagctttctg ccttttccct  13500 

atctaacagg cctaaggtga tactacattg tggttttaac ttgtatttct ctctgatttt  13560 

tagaatctct ttatacattc cttggctttg ggtgcattct tgttttttgc gggggttggt  13620 

gatttttatc aaatcaagga cagacatccc attctaatcc tagtttgcta taggaatttt  13680 

gtgggggctt tttggtagag acagggtctt gctatgtttg cccaggcggg tctcaaactt  13740 

ccgggtttaa gcaagcctct tgcctcagcc tctgaaggtg ctgggattac aagcatgagt  13800 

caccatgcct ggccaagagt ttttaaatta taaattgttc aatcttatca aatccttttt  13860 

ctatgttgaa tgaaataatt gcctagctgc tttcaaaagt gaaacgtgac tttgtgaata  13920 

tttctaaagt acaaaatact tggaggacag ccatttattg tcacaacttg gctttgtagt  13980 

ttgtttttgt ttttgttttt taacatttgg aaaccatacc tatgtgttaa gtaagtggct  14040 

tgtgatttaa ggaatagaat gcatgtaagg gcacacttct tttgttttac agaagggatc  14100 

aagttctgtt caggaagatt tgaaacatag tgtaaagttg ttgctgtttt aaacttgtaa  14160 

acctgattct tctcatgtgg gaggtacgta agtaggcctc tcagatttca ggttggttct  14220 

ctgcctggta gatacaaggg caaaactatt ctggaaccat attgatgtta aaaaaatttt  14280 

ttacggactt cctgccggca aggatttttt taaaagattt tttaaatgtg tctaagaaat  14340 

gttttaattt gtcttctgat tatacagtga tttacaattc atgcttcttt tatatgtggg  14400 

caaaattaag aactaatatg taaaacaaaa tggagcacat tcccattttt cttattgctt  14460 

tgagttgata tggcccctat gtcagtagtg ctttggctga acgtcacaaa gacctaacac  14520 

agtgccctaa acaaataggg ggtttgtttt tctccaaaaa gaaatttggg gtagggtgcg  14580 

gtggctcaca cctgtaatcc cagcactttg ggaggccaag gcgggtggat cacgaggtca  14640 

ggagatcgag accacggtga aacctcgtct ctactaaaaa tacgaaaaaa attagccggg  14700 

cacggtggcg ggtacctgta gtcccagcta ctcgggaggc tgaggccaga gaatggcgtg  14760 

aacccgggag gcggagcttg cagtgaatcg agatggcgcc actgcactcc agcctggggc  14820 

aacagagtga gactccatct caaaaaaaaa aaaagaaaaa aaaaaaaaag aaaggaattt  14880 

ggaggtatgc agcgtctagc tttggatcag cagttcagta atattggagt tggtggtatt  14940 

ttaaggtagt tttgtctttt ctgtcatgtt tgagaccctg tagctacagg ataatgtttt  15000 

acagttacag ctacatggtt gcattcaagg aaggaggaag gaactgtact ggcaactctg  15060 

tccttacccc cccaccctcc tttttttttt ttgagatgaa gtttctgtca ctcaggctgg  15120 

agtgcagtgg cggaatctca gctcactgca actgtcgcct cccttgttca agcgattctc  15180 

atgcctcagt cttctgagta gctgggatta caggcatgtg ccaccatgcc tggctaattt  15240 

ttgtactttt agtagagatg gggtttcacc atgttggcca ggcaggtctc aaactcctga  15300 

cctcaggtga tctgctagcc ttggcctccc aaagtgctgg gattacaggt gtgagccaca  15360 

gtgcccggcc tcccctttta tgataaacaa aggcattacc aacccctacc ccctactaca  15420 

ttgccaccta gtagacttta actaatgaga actggccaga actaagccag atggctatct  15480 

ctagctgcag agaagtttgg gaaaacaagt atttggccaa tgtggtctcc ctaaacacgt  15540 

gttcaacttc ttgaagaagg aaatctcatg tctttggctg tattcagcat ttttcagtag  15600 

cagttacata ttctagtttt catggtggat gaagtggtac cagcttagtt ccacaggagg  15660 

gagaagaatc aggactcatt taatccataa gaattaaact cagcagcttt tgagtaccca  15720 

ttatgtgcat agtctgccat gaaatattat aaagtagtcc aggtatggtg gcttacacct  15780 

gtaatatcag cactttggga gaataagaca ggaggattgc ttgaggccag agtttgagat  15840 

cagcctgggc aacatagtga gatcctatct ctacaaaaaa ttaaaacatc agccatgtgt  15900 

ggtgtacgca cctgtagtac cagctactaa ggaggctgag gtgggatgat cccttgagtc  15960 

caggagttcg aggctgcagt gaggtatgat cgatcacact actgtactcc agcctgggca  16020 

acagaacgag accctgtctc aaaaaaaaaa aaaaaaaaaa gttatcaaag aattatataa  16080 

cattttgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtatgcag gttgtttatt  16140 

ggctccttag gaagaaaaaa atacgtgtat gaaataattg attaacagta caagaactca  16200 

taattatttg tttaaatgtt taatgttggt actgagtgct gtggcatagg aatagggaac  16260 

tttttcttag ggtcggtgat ggattcttgg gaaaataaaa tgaagggcaa atggaagcaa  16320 

aagacaattt aatttgcttc tgttttaagg gaacttttaa aaagttaatt cttaaatttt  16380 

ttaatttaag gacttcgtca agaaacatcg aattaaatat attgagttta accctaacaa  16440 

gcatcagatc tttcagtctg ctgtatgagg aaatacaagt ttctttctgc tttctattat  16500 

gattgttgat ttgcatgagc gtgttttagg ttaggctgtg ttatgctgtg gtaatacata  16560 

ccaccaacat cctcatgatt taacacaata aaaaacttct gctcacacca agtctgcttg  16620 

agggctcatt ggctccgtgg aaactgatct ccatgtccag gccagtttgg tcttgtggcc  16680 

gtccgtttta gggcagtgct tagggtcagg agagcaaaac acagggctgg agagttaagc  16740 

acaggcaact aaatgcttca gcatgggaat ggcattcatt ttcactcaca ggatgtgttc  16800 

agcttagtca catggctgtc tatgcctaac ctcaagggaa gggagtgcag tcctccagga  16860 

actcagatgt aaaaaagcca gtatgatgga tatagtattg tctacaaaaa aaagtagcat  16920 

aatagagtta gatacaagca aagtactcta ggatcccagt aaggagaagt aagaaattct  16980 

gatgagatgc agggagagcc ttagaagggt tcatgaagat ggtgacagat gatacaaact  17040 

cagtagaatg agcaggtttt tcttagattt gaagagaaga aaggacattc aaactaaggg  17100 

aacaacactg actgagtcag agctagactc aaagctagag tctactggct gatgtcgtgg  17160 

gagaggaaga agagatgagc gggccttgaa ttcgtttaac attcagcaaa aatgtattgc  17220 

atgtctacca tgtgttaggc actgtttcag gtttggggaa tatctgataa tgaacaaaac  17280 

acaaaaagcc tgtccttgtg aaggttacat gctagtggaa gaagcgctaa ggagttagta  17340 

ttttattata agcacactgg tgagtaagca aagataggaa cattggatgc ctgtgaatct  17400 

taagattttc ctggccgagc gcggtggctc atgcctgtaa tcccagcact ttgggaggct  17460 

gaggtgggta gatcacttaa ggtcaggagt tcgagactag cctggccaac atagtgaaac  17520 

cctgtctcta ctaaaaatac aaaaattagc cgggtatggt ggcgcgcacc tgagtcccag  17580 

ctactcatga ggctgaggca ggagaattgc ttcaacctgg gaggcggagg ttgcagtgag  17640 

ctgagattgc gccactgcac tccagctgac agagtgagac tccatctcaa aaaaaaaaag  17700 

gatttttcta agatttctat tttacattaa atagaaggca gttggtttgc atgaaaatta  17760 

ttatttcatc aatttgactg cctcattata gaaaacacat attgaagtca aataaaacgt  17820 

agagatgaat ctctgaagtt aaaatatgtt atttgggacg caagaattgc aatttggggc  17880 

acacagacca cagggtggtc ttcagtatgt atgaagaaca aagtaaagga tggaggtttt  17940 

ataaagagaa gtgttacata ttttgaaaga caggtcattg gcactagtaa agttttgggg  18000 

aggtggcaag ccctgattgg tgagtgacag tggtgggtaa tactggtctt agagtcagca  18060 

acaagttgtt tcagtagcca ttagataaac tggtttcagg ttacaatagg cagtttcagc  18120 

agccaggctt acagagaatt ataatcttgg agcaatgtta catccctccc cctcccctgg  18180 

ccccccaccc catccctgcc cctcagctct gatttagttg agtacgaata ggatgaccca  18240 

attagtatga tcagctttca cacatgaagg ttgaatttat gaaacatgta aatttgaaaa  18300 

tacatgttta cattgcaaaa agctttttta acaaaaattt tggccagtag tataaattca  18360 

gtgaatatgt tttcattgca cagatagtaa aaccacttga tacatacctc atggggatat  18420 

ggactgcttt atgcgctgct ttttaccaca ccttaaatag tgcctggttg tgtgtgtgtg  18480 

tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtaactc agtaaatatt caatgaatga  18540 

atgaagaaat tcagaagata aaaaagagaa atttccctta tttttaacct tctgaacact  18600 

atagtggtta gcatttatat catttattca gccattctaa tatttattga gtagcagttt  18660 

tgtaccaact gctgttctaa gatataagga ataataaatt cctgttactg ttttcatgaa  18720 

acttaaattc tagtgtaatt aaaatcatgt agaaataaac ataaacatga tcacccagct  18780 

tcttttaaaa ctagactgca gttgatgtaa taatttgcat tacaacagca tgcatcttgt  18840 

gcacaacaaa atctacctgt ttttgtatta aagccttagt gtcaaagctt tattatcatt  18900 

ttagtctttt atcaactcca tatttataaa tggtctattt tcccaaagtt ctaatatgga  18960 

aatcagaatc atttttgtta gaggaacaat gtttacaagt tgcctagatt tgcagtgagg  19020 

tcataaaaag cctgtttaat ctaaaataga catttgcaat aaaaacagaa attgttgttg  19080 

agatgccata ttatgtgata actgagtaaa acagacaaga gcctatcccc taacctggta  19140 

tgtgaatgtg aaaatattag agaaataatg aagaagtaga tggagactaa tgaggaaatt  19200 

ctgaaaagga catcttttga gaaattcaga ggtagatggc gcaagtttta aagcttactt  19260 

tcactttaaa acacctgagt ttcatttcct ttgatttgag taaattacaa agcagtttat  19320 

tagttaaatc aggcttgttt tgatttatag gtatatagag aaagacagga cattttcctg  19380 

gacagaaagt tggaaaagag aaacgtgtaa agggggtgga aagtggctgt gagtgcatgt  19440 

ggaatgagaa gcctcccttg ggcaggagtt aacagccaca atggggaaag gattgggaca  19500 

tctaatcctt tgagtgtgtg tgggggccaa gggagcagta gtagcaggat gcctgcgcat  19560 

acagccatgt acacagtgtg tacacagaag tgtaattctt gggcctgaat atttcatagg  19620 

gtagagacat attgagtact ttattaagta agcatattga gtactttatt catctataca  19680 

acaagggtcg tctattaagg gccacacagt ctagctgttt ctgtaaagca cattgttttg  19740 

aattactgtt agcagtgtag tatagaagga aatcgggaat ccagattctc tatggatttc  19800 

cccctgaaca gttatgtggc tgtatcctta tctagtgaat ggtgacatta gcttttcccc  19860 

tgctgcacgg gctgtagtga ggctcaggtg tgcaggtgca cttactaaca tatggaaaag  19920 

ttaagcactg tataaccaga aggtagccct tttactccta ttttatatga cagccacgta  19980 

tgcaaaatat ctaatttctt cctgaacact caattgaact tcaacacttc gtatttttcg  20040 

tctcagaatt tttattttcc tcaaatttat attatgtggt taaattcctt tgaagtgcta  20100 

gatactttaa gattaaaatt aaagtaggaa tgttttttct tcaattagaa gctcttagaa  20160 

cttggcaagt actctgtgtt ctctcatttc cttatctttg tgtatgctgt attgcagcac  20220 

acgtcacatg gagatgggcg tcaagaagtt acctctcgta ccagccgctc aggagctcgg  20280 

tgtagaaact ctatagcctc ctgtgcagat gaacaacctc acatcggaaa ctacagactg  20340 

ttgaaaacaa tcggcaaggg gaattttgca aaagtaaaat tggcaagaca tatccttaca  20400 

ggcagagagg taaataccag ttatgcttat ttctgttatg acagttgctc tgtttatttc  20460 

catgtaagag aaagaaaaga atatagatat aggccttatt tctttttttt aagatggagt  20520 

ctcgctctgt cacccaggct ggagtgcagt ggcatgatct cagctcactg caaactctgc  20580 

ctcccgggtt cacaccattc tcctgcctca gcctcccgag tagctggcag tacaggtgcc  20640 

cgccaccaca cccagctaat tttttgtaga gacagggttt caccgtgtta gccaggatgg  20700 

tctcgatctc ctgaccttgt gatccgcccg tctcggcctc ccaaagtgct gggattacag  20760 

gcgtgagcca tagcgcctgt aatatatagc tactatgtat tacatgtatt acatgtcaag  20820 

ttctaaccac ataatataaa tttgtaatac atagctggga ttacaggcgc acaccaccac  20880 

accacgctaa tttttttttt tttttgtatt tttgtatttt tgtagagacg gggtttcacc  20940 

atgttggtca ggctggtctc gaactcctga cctcgtgatc cacctgcctt ggcctcccaa  21000 

agtgctggga ttacaggcat gagccaccgt gcccaaccta ttttattttc aagacagggc  21060 

cttgccctgt cacccgagct ggagtgcagt ggctcaatca tggctcacta tagcctcaac  21120 

ctcctggggt caggcagttc tcccacctca gcctctcgag tagctgagac tacaggcatg  21180 

cactgccaca cccggctaat gtttaaaaaa tttttttgta gagacagggt tctcaccgtg  21240 

ttgcccaggc tggtcttgaa ctcctgtgtt caagcagtcc tcctgcctca acctcccaga  21300 

gtgttgggat tacaggcatg agccaccatg cctcactaat taagcttttt cttttttggg  21360 

gggttagggg ggtgtcgggg gttgggacgg agtcttgccc tgtagcccag gcctggagtg  21420 

aagtggcatg gtctcggctc tctgcaacct ccgcctccca ggttcaagcg tttctcttgc  21480 

ctcagcctcc tgagtagctg agattacagg cgcacaccac cacgcctggc taattatttt  21540 

tttttttttt gtatttttag tagaggtggg gtttcaccat gttagtcagg ctggtttcaa  21600 

actcctgacc tcaggtgatc tgcccgcctc agcctcccaa agtgctggga ttataggcat  21660 

gagccaccac gcccagccta attaagcttt ctcaaaagaa catgaaacat atattaggtg  21720 

tctgggagtt ttttgttttg tttttgtttt tgtttttttt ctgaggcaga gtctcactct  21780 

gtcacccagg ctggagtgca gtggtgcaat ctcggctcac tgcaagctcc gccttctggg  21840 

ttcaagccat tctcctgcct cagcctcctg agtagctggg attataggca tgagccacca  21900 

cgcccagcct aattaagctt tctcaaaaga acatgaaaca tatattaggt gtttgggagt  21960 

tttttgtttt gtttttgttt ttgttttttt tatgaggcag agtctcactc tgtcacccag  22020 

gctggagtgc agtggtgcaa tctcggctca ctgcaagctc cgccttctgg gttcacgcca  22080 

ttctcctgcc tcagcctccc gagtagctgg gactacaggc atccaccact gcacccggct  22140 

aattttttgt atttttagta gagacggggt ttcactgtgt tagccaggat ggtctcgatc  22200 

tcatctcgtg atccgcctgc ctcagcctcc cacagtgctg ggattacagg cgtgagccac  22260 

cacgcctggc ccatctggga gttcttttgc tttcccatta ctttaaacgt tggaaatatc  22320 

atagagtgtt taaatagtct ttacctttaa aaataggtaa tgttttgttc tttttcagta  22380 

gcaaatgtct gctaccacag taaaaattgt ctttaacttc aggtatacac ttatgtgtat  22440 

gagctcatgt tacttgctaa tcaatattat tgtcaatatt tacagattta tcttcaagaa  22500 

gtttcttaat ctctctactt ttctcatagc gtatgtttaa tcggttattg tgtaggaagg  22560 

cacatacttt cctaaccttt gtgaaatggc tttctgctca gccccgttcc tattaatcaa  22620 

aaatacatgc attaaaacca caaaactaac tccctcctct tgttatactc atatggtaca  22680 

gagcctgttt tgcctctttt tttttttttt tttttttttt tgagacggag tctagctctg  22740 

tcgccaggct ggagtgcagt ggtgtgatct cagctccctg taacctccgc ctcctgggtt  22800 

caagcaattc tcctgcctca gcctcctgag tagctgggac tataggcgtg cgccaccatg  22860 

cccggctaat ttttgtattt ttagtagaga tggggtttca ccatgttggc caggatggtc  22920 

tcaatctctt gacctggtga tctgcccgcc tcaacctccc aaaatgctgg gattgcaggt  22980 

gtaagccagc gtgcccaacc tttgatgtag tttcttgcat ttaggtcttt gcgcctgctt  23040 

ttccctgtac ctgaaatact ctttactctt ctgtttaggg aacatttctg agaagtaatc  23100 

attgacaaat cccctttccc caggcatggg attccataaa aatcccgata ctccccttat  23160 

atggcacaat ttacattgta ttggaattgc tcgtttgtct gtctccttct ctagtttgta  23220 

ggctgtctcc agtctgtagg ggaagatgac agaacttaac acagtgcttg gaacctgtta  23280 

ggtacttaat aaatatttgc taaatgaatg caataatact gttttttggc gggggggagg  23340 

tggtgttggc aacagagtct cactgttgcc caggctggag tgcagtggcg tgatctcagc  23400 

tcactgcaac ctcccgcctc ctgggttcaa gcgattctcc tgccttagcc tcccgagtag  23460 

ctgggattac aggcacacgc caccgcaccc agcgaatttt ttgtattttt agtagagagg  23520 

gggtttcacc atgttggcca ggctggtctc gaactcctga tgtcaggtga tccacccacc  23580 

tcagcctccc agagtgctgg gattacaggc gtgagccacc atgcctggcc tgaatgtagt  23640 

aatacttttg aaggaagctt ttaaaacaaa tgctctccct gtgcgagacc cttctgatag  23700 

atgtgccaag actgtgacac atatggcgta gcattcatgc ctgcagccca ccaggcctgg  23760 

ggctgcaaga gcatgagccc tgggtctgtc atctgtcagc atgcatcctc tgtttgcagc  23820 

aatgtgccct gtaaatattt tcatttcctg tgtgtgcgga gacttggaaa aggttgggaa  23880 

gcactggact gtgctaactg gaattttaaa agactgttgc cagaaatttg ccttttgaca  23940 

attcattaat tttagtgata aaattcttgt ggatttttag ttaagactcc ttgttgctga  24000 

gctgccttat agactgcttt tggaatctgt aaacagcttg tgtgggcgga gctgtccttg  24060 

ttgtccttga ttaaagcttt cttgagataa ggaacggtga gacctctgag tttcttagtt  24120 

cccaccagtt ccaggtggct acttgccagc ttcctcatgt gggcagagat ggtgggccaa  24180 

gagagcgttg agacagacga acctcttcca tttaccttac ctgatttaca ttatctagag  24240 

tctggcctgt ggtgtttact tctagtaggt tctttctcta gaaatgcttg aatatgacta  24300 

gcagagtggt ttaatttaaa aactttctca gtttctcagt ttttttaaaa ctttgaacaa  24360 

gttctcactc gtaagtggag ttgaacaatg agaacacatg gacacaggga ggggaacatc  24420 

acacaccagg gcctgtcggg gtgaggggca aggggaggga tagcattagg agaaacacct  24480 

aatgtagctg atgggtcgat gggcgcagca aaccaccatg gcacatgtat acctgtttaa  24540 

cctgcacgtt ctgcacatgt atcccagaac ttaaagtaaa aaaaaaaaaa aaaaaaaaaa  24600 

aaaaaaagga aaaactttga acaaaatcat tttactcttg tggggttttt tttgcctatt  24660 

gtagatatga catataaaat gtaaacatta tagaaatata gaaattcatt atgtagaaag  24720 

taagttcctt gaaatttgtc tcttcaaaga caatcacttt cagcagtttg gtgtatattc  24780 

ccagagtttt ttatatagac attaactttt aaaaaatttt aacagaaagg gactcatgga  24840 

acatgatgac agttttttta cttagtaatg taccttgacc atgtctgggt cttagtactc  24900 

atagatctga catattagtc taaaggcagc atagtcttcc tggctatggt ggtaccatag  24960 

tttatttcct atcagtgggc attagggttg tttctaaatt tttgttgtta caaacagatc  25020 

tgcagtggac attctttagc attgcgtgtc cttgttaagt gtttctgtag gataattcct  25080 

agaaatggaa gtcctgggtg aaagtggatg actatttgac attgtaatag atactactaa  25140 

attggttttg aataaaaagt gatgtaccta ctttattatt ctaccaaaat ggaatagagt  25200 

gttcattttc gtacatgctt ctacactgta gataattttt gtctatctga aggtctcaat  25260 

ctgtttttgc tgctgtaaca caataccagg gactaggtaa tttataaaga taagaaattt  25320 

atttcttaca attgtggagg ctgggaagtc caagatccag gggctgcatc tggccagggc  25380 

cttcttgata catgaagggc gtgatggaag ggcaaagagt ggggaaggaa gggaagagga  25440 

ggagaaagga agaaaagagg gcagagccct tgcaatctga ttgcctctcc agggccccat  25500 

gccttagtac tgctgcaaca gcaattacgt ttcaccatga gtttgggagg ggacattcat  25560 

tcaaaccata gcacgtatgg acaaaaaaag ggtgtagaga aaaccagaag ttgctttttc  25620 

ccttttcact acttagattt atgatctttt tatatatttt tgtcattcat aatttctttt  25680 

tgaggcaagt tccctggcca cccgcagtag ctcatgcctg tattcatagt gctttgggag  25740 

gccaaggcaa ggaggatcac ttgagcccag gagtacaaga ctgcattgtg ctatgattgt  25800 

accgctgtac tccagccggg gcaacagagg acactctcta aaataaataa aaataaaaca  25860 

agtttcctgt ttatatcctt tattcatttt tctttttttt taatcttagt gatttaaacc  25920 

ctttatgttt cagtcatctg tctgatgtgt ctgttaatgt aggttatgaa tatctttccc  25980 

tagattactc cttttaactg tttatgatgt ctttcttgtt ttagggaagt ttttaagtat  26040 

ttatgtggca aaatcattta atctttttct ttattacatt tgggtttcat gtcttcttga  26100 

agatttgtcc cgtgacttaa aaaacagttc tataggccgg gtgcagtggc tcacgcctgt  26160 

aatcccagca ctttgggagg ccgaggtggg tggatcacga ggtcaggaga tcgagaccat  26220 

cctggataac acggtgaaac cctgtctcta ctaaaaatac aaaaaattag ctgggcatgg  26280 

tggcgggcgc ctgtagcccc agctgttcag gaggctaagg cgggagaatg gcatgaaccc  26340 

gggagacgga gcttgcagtg agctgagact gcatcactgc actgcagcct gggtgacaga  26400 

gtgagactcc gtctcgaaaa aacaaacaaa caaacaaaaa accagttttg tattttcttc  26460 

taatactcct cctatggctc acattttaac gtttaattca tgtggtatgt atttgggaag  26520 

attagtatta ggtgtaggga tctgactttt tttttccact tggattacaa ttgtcccaga  26580 

accatcagtt ctctcccaac aattgaagat acctgcgtta acacataata aattctcata  26640 

tgtgtcctgt tatttctcca gtctgtttat ttagtcctat acccatactg tggtgttttt  26700 

attactgcag ctgtggattg tatgttttag gtcaagttcc cctcctgatg attctttttt  26760 

ttttctctct ctcttttttt ggtgagatgg agtctcgctc tgtcgctagg ctggagtgca  26820 

gtggcgggat ctcggctaac tgcaacctcc acctcccggg tttaagcaat tcgcctgcct  26880 

cagcctcctg agtaagtggg attacaggtg tgtgccacca cgcccagcta atttttgtat  26940 

ttttagtaga gaggggattt catcatgttg gccaggatgg tctcgatctc ttgaacccat  27000 

gaactgccca cctcagcctc ctaaagtgct gggattacag gtgtgagcca ccacgcccgg  27060 

ccaatgactc ttatttttca aaattttcat agcttttttt tttttttggt catttactct  27120 

tccacatgaa ttttagaatt aagttgccat tttctaaaaa cagagcatga aattttgatt  27180 

agattagttt tcatgggatt agttggtttt ttgttttttg ttttttttac tagtagcagt  27240 

agaatctttt caaatatgcc ttaatatagg cgctggggct tgcccgtggt gctcttgata  27300 

tataaggccc ggacattctg ccagtttttt ctcgagcagt gacaccaaga agttaacagc  27360 

caggtgaatg ttatgcacaa gctcatcgtc tgtcatcttc acgtggccaa cagccacagc  27420 

caaacataac atgttcatat gaaacttgat tgtggacttc gcctcatcca ctttggccac  27480 

cgtgttttca tcgtgtgtga gcagggaagg gaactttact gcctttgtta ggcctatgcc  27540 

gaggattcgt gggatttgct ttatcagaga ctctgaagcc aaaaatgcat catacttctt  27600 

ggccagcttc ttgaccagat tcttattctt gagttttttt ggcacctcag tgtccacttg  27660 

gggggatatc cgtggccttg gtctcgtcac agtgctgctg ttcccccagg acccacactt  27720 

gggacaggga gtggacttaa gcctgacggt gcccgagaag cgcttgtcct tctgggggtc  27780 

atagttcttc aagctgatct gcaactccac catcttcagg aacttggggc actttcactg  27840 

gttcccgtgc aggacttcct gcaccgcctc atccagggtg tcgtgagaga ctttgctgct  27900 

tatgggttct catgccacgc taaccagaaa agagggttta gttggtttta taaattatta  27960 

atagtttggg aggaaattga tattttaatg atgccaagtc tttctttctt ttttttcttt  28020 

cttttttttt tttgagacgg aatttcgctc ttgttgccca ggctagagtg cagtggcgtg  28080 

atctcagctc accacaacct ccgcctcctg ggttcaagca attctcccac ctcagcctcc  28140 

cgagtagctg ggattacagg catgcaccac catgcccggc taatttttgt atttttagta  28200 

gagacgggtt tctccatgtt ggtcagactg gtctcaaact cccaacctca ggtgatccac  28260 

ccgcctcggc ctcccaaagt gctgggatta ccagtgtaag ccaccacatc cggctaatgc  28320 

caaatgtttc tattcaggaa tgtgcatgtg tctcaaattt gttttcaggt tttgtaactt  28380 

ttttcatcta tgttttatat aatgcttgtt aaattcattt caagctattt tataattttt  28440 

gttgctaatg taaatggaac ttttttttcc tcaagaaggc aataatcata taacttcttg  28500 

catttgggaa acttttgatc tctcatttgg aatgtcgaaa attaagttta tattgttttt  28560 

taatagcatg cttttttttt ttttttgaga cagagtctgg ctctgtcgcc caggctggag  28620 

tgcagcgcga tctcggctca ctgcaagctc caccttttgg actcaagcaa cctcccactt  28680 

cagcctcccc agtagctggg accacaagca cacagtaccg cacctggctt attttatttt  28740 

attttatttt atttatttat tttattttat tttatttttg gtagagatgg agtttcacca  28800 

tattgcccag gctggtcttg aactcctgag cttaagcagt ccgcctgcct cggcctccca  28860 

aagtgctgag attacaggcg tgagccacca cgcctggtca gttgtctttt tttgagaatg  28920 

tcaaataaaa tgggatcata tggtatgtaa ccttttgaaa ctggcttctt ctcactcagc  28980 

atcatgtctt tgagattgat tcaggctgtt gcatatattg acagtttgtt cctttttgtt  29040 

gctgagaagt attctgttgt atggctgtgc tacagttggt attagctccc ccactgaagg  29100 

acatttgaat agtttccagt gtttggcaat tatgaataga actcctgtac aggtttttct  29160 

gtgaacataa gttttaattt ctctaggagt gacattactg gatcgtgtgg taaagaatta  29220 

agtgaattgt taactagaaa actgatttta tataacagta taatattcct agtagaaaga  29280 

aacctaaagc ctctggtctg gtctgtgaat tggtgtattt ttattactta gtacttttct  29340 

tttctttctt tttttttttt tttaaagatg gacttttgct cttgttgccc aggctggagt  29400 

gcaatggctc aatctcagct caccgcaacc tccacctccc aggttcaagc gattcccctg  29460 

cctcagcctc cctagtagct gggattacag gcatgtgcca ccatgcccag ctaattttgt  29520 

atttttagta aagacagagt ttctccatgt tggtcaggct ggtcttgaac tcccgacctc  29580 

agatgatccg cccgccttgg cctccccagg tgctgggatt acaggcatga gccaccacac  29640 

ccagctactt agtacttttc tcagctaaga tctttatttt tgtcagcgtt ctcttgccct  29700 

gtgatgggaa cgtgatgtat cttgcctatt gaagaactaa aacctctgaa gaaaacccag  29760 

agggttgtgg gaagagtggc attgatgatt tggggactta atttgttctg agtcagtata  29820 

agttaaaggc ttattgtgta ttatgttgag agttttaact gctatccttg gggtaagaac  29880 

agagatgtag aattatatcg tgaaaagaat tttctgaaag aagggagtag ggacaatcta  29940 

tatcatgcat ttaagtcaca aggatgtcgt gaacataaaa gatactcacg aaggccgggc  30000 

atggtggctc atgcctgtaa ttccagcact ttaggaggcc aaggtgggca gatcacaagg  30060 

tcaagagatc gagacctgag gtcaggagtt tgggaccagc ctggccaaca tggcaaaatc  30120 

ccatctctac taaaaataca aaaaatagcc ggggatggtg gtgtgcgcct gtagtcccag  30180 

ctactcggga ggctgaggca ggagaatcac ttgaacccgg gaggcggagg ttgcagtgag  30240 

ccaagatcat gccagtacac tccagcctgg caacagagta agaccttgtc tcaaaaaaaa  30300 

aaaaaaaaaa aaaaaaagat actcatgaaa aactatatgt tcgttggaag aaagttgttt  30360 

taatttaaca aacatgttgg aataagaatt ataaacaaga tacattaata tgtacactct  30420 

gaagaccatt ttaaatcaag cctttaaata gcctagttat ggtgtaagtt cagtttagat  30480 

gagacttccc acaggatgac catgaaccaa tcagaaatgg atatcaaaat gctcatttta  30540 

tatattttta aaatacatgt accagttgtg aaattcatct gatttagctc ttaaatgaaa  30600 

atgctaccca ttatccatat tgtcctggaa gcatctatcc catatttact atgaatctgg  30660 

ggatgttagt tgcatctgct gtcttgcttt tgaccaactt ttcatagctt atggttattt  30720 

tggtgtgaaa tattgcctgt tttacaccac agttttcttt caagttcatt attttccccc  30780 

cactaatttt catagcctcc cagagacctt tcccctcaca cgaactacag aactcacttg  30840 

tttcagtcat ttgtacttta ttggagttat ttattgttta aaaattattt tcctaaagta  30900 

atgcatgcac atagcttaac aagtcaaata tactaaaaag ttctaatgac aatcagaagt  30960 

ttcttttctt atccctcttt ttcctcagca ttattactca aaggccccaa cttttttaag  31020 

ctctttcttc tgttactcca atagctttct ccaaatttat cattttaaac atcattgact  31080 

tccacttccc acttccatat ctacatttct ttccctagct tttctattgc agtgatatat  31140 

ttggcttatt tacttaaatt acgactgtgt aagtattgtt gagctttggc tatgatcatt  31200 

tattttctta tataattgta aagctttgtc taaaattaat agttgtttct ttttctataa  31260 

actcttaggt tttatgtgtt actgctaatt ggccaaaatg ttctagctta tctttcaaat  31320 

attttgcagt actcacacat ataatataat gtattagctc aagagagaat cggtgagtat  31380 

aaattagaga cagcaaggta gctctttcta ggcacagata agtgggatgg tagctacagg  31440 

gagacattag gccaaggtat tttttagaag atggacaaaa tatcaacata tttctctact  31500 

aatggggata atctcataaa aaggaggaaa ttggtgctgt cgaagagatt ttggaatagg  31560 

tgaggggatg gtggaggcat tggtctttgg ataacatgga cagttcttcc atagaaatag  31620 

gaggaaagca agccaggcgt ggtggatcac gcctgtaatc cctgcacttc gggaggccga  31680 

agcgagtgga tcacctgata tcaggagttc gagaccagcc tggccaacat ggtgaaacct  31740 

catctctact aaaaatacaa aaaattatct gggcatggtg gcgtgcccct gtaatcccag  31800 

ctactcagga agctgaggca ggcgaattgc ttgaacccag gaggcagagg ttgtggtgag  31860 

ccgagatcgc accactgcag tccagcctgg gcaacaagag caaaactctg tctcaaaaaa  31920 

taaagaaaga aaataaagta aagaaatagg aggaaagcag agggtgccgg catcagtgca  31980 

ggtgagggga tccttatggt agtaggagct tgtagaaatt ttctgagtgc aaactgtttt  32040 

ttcagtaaaa tggaaagcaa actgatctgc tacgatgagg agatgtatta gagatgtgag  32100 

gaggttaaaa taattgccag ataagcagga gagtgaatgg actagagaaa tgtaatagaa  32160 

ttgccaggca gccttaaggc ttccctgagg ttggtgacca aggatttaaa gtgggaagag  32220 

tcagcatggc gttgtgctac tctccagcca cattcagttg cccagctgca ggcatggcat  32280 

ttgcagagat tggggttttg tcacattagt atagtgaaag gacaaaggag cattgttata  32340 

caacacccca ggagcattgt tatacaacaa catcacaatg aaattagtga tataattagg  32400 

aactaagaac ttgaggagga agactgaccc tatgaaggtg tggggtcagt gaattacaga  32460 

tcctggtaag ttccaacagt tattagagta ctagattgag tgagcaggaa ggtagaagaa  32520 

gttagttaaa gaatgggaag ctcaaacttg gatcatgaaa ggttttcaga tattgggaat  32580 

gtcaaagact ggagtataac catgtaagta gcttaagtat gtaatatttt ttttctttct  32640 

ggaagtttat ccttggtttt tagaaattag ccattgaggt gccaagggtt agtcttcatt  32700 

cattgttctt ggtgctcatt ggaccctttt aatatagagg tttttgtctt tcagttctgg  32760 

aaaattgtct cttttttaac ttaaaaatct tcattctgga atccttaagc agagactgga  32820 

gtgcttgaaa agagcctcaa aatctatctt ctatctctat gtttttactt tctgggagat  32880 

atttttaact tcatcttcca ttctttctgt taaaaatgtg tgtgtgggcc gggcacggtg  32940 

actcatgcct gtaatctcag cacttgggga ggctaaggca gaagtgtcac ttgaggtcag  33000 

gagtttgaga ccagcctggt caacatggtg aaaccctgcc tctactaaaa atccaaaaaa  33060 

attagctggg cgtggtggcg cgcacctgta atcccagcta ctcaggaggc tgaggcagga  33120 

aaatctcttg aacccgggag gcagaggttg cagtgagccg agatcgcgcc actgcactcc  33180 

agcctgggtg acagagcaaa actctgtctc aaaagaaaga aagctgtgtg tgtgtctcct  33240 

cttctctccc cagctcactc tttgatcatt ttcatctgtt tgttgttact gtctttacag  33300 

catctagccc tggtattatg aatgttgttt cttctgctga ctccctgaga atagtaaagg  33360 

cttttttttt tttttttttt ttttagctct tttataaagt agatttttgt tccctgcatt  33420 

gcttctcttt ttttctgggg ttctttcttg ttaccgctct ttcatataga gactttctct  33480 

ggatgtctgg tagcctctgg ttgtctgtac ctaatgtgga gccctaagca tctgatcaca  33540 

agctgtgttt gtatgaatag gacatgtttg accacagagc tttcctattg ggagttgtct  33600 

ggtgctttta ttgaagaccc cagatatttg tgtccttaga tttctgagag tatccagttt  33660 

ctctagataa gaatcttctc ttctgcctgg gaggaactga tgatcccacc cctcagtcac  33720 

ttagtcctcc cccgcctgcc ttttcatctg ttgcttcact cctgaaacca cgtttcttca  33780 

tcctggggtg tgtgaaactt cctgagactt tgcataaatg cttatgttta gtcacgagtt  33840 

tgttggtgaa gactatgtta acaactttac agaaagtttg gagaatagag aagaaaaacc  33900 

ccacaatcct aatattctga ataccatttt tgtttttgta tattttccat atacatgttt  33960 

tttcaacata tttttgatta taattttgta tcttgttttt tccgccctcg gaattttatc  34020 

caaagcagtt ttctacgttg ccactaatcg tcataattgt tcatttcagt ggttgtgtac  34080 

aatgccattg atgagaacag cagttctcaa acgtttctgt ctcagaactc ctttaaattg  34140 

aaaattgagg ctgggcgcgg tggctcacgc ctgtaatccc agcactttgg gaggctgagg  34200 

cgggcggatc acgaggtcag gagatcgaga ccatcctggc taacatggtg aaaccccgtc  34260 

tctactaaaa atacgaaaac aaaattagct gggcgtggtg gcgggcgcct gtagtcccag  34320 

ctaccaggag gctgaggtgg gagaatggcg tgaacccggg aggtggagct tgcagtgagc  34380 

cgagattgta ccactgtact ccagcctggg tgacagagcg agaccccgtc tcataaataa  34440 

ataaataaat agaaaattga gaactcccca aagcttttat ttattagggt tatatgtatt  34500 

gatagctgct gaattggaag ttattactta ggaaacttaa aatatatatt aattcatcaa  34560 

aaataataat cctgttacat ggtaatgtaa ataacatatt tttatgaaaa acaactattt  34620 

tccaaagcaa attattgaaa agagtgaatt gtttaaattc tttgcaaacc cctttaatat  34680 

ctggcttaat agaagttagc tgggttcctg tgtctgctct gcattcacac tatttaagta  34740 

tgttgttttg gttgaagtgt ataaagaaat gtagctacaa aaggaaggga gcatattaat  34800 

accttttcag gtgattgtgg atattgttct ttgacattat accaaaactc agcaagtggt  34860 

ttcttggggg tgggtagaca gtgatgaatt tttattcaaa acaactgtag tgactgacaa  34920 

aaaaagttaa aacccagaat gatttgcttc aattaaaaat taattatatc ccaagagcag  34980 

gggtctacca ggttgtctga ggggaggggt gaactggccc agaaacggag caggtcaaaa  35040 

ttcctctgct gatcagtggg atggggattg ggatcaagat tgcttctgtg aatagccact  35100 

gcctggggaa catagcgaga tcctgtctct taagaaaaag aaacagaaac ttttggaaac  35160 

aagcagacaa gggtgaaaga aagccttggt gtaagatata atttatatat tccatataag  35220 

atatagaata catatgttat ataactaaaa agcataaaaa cagtcagcat gcttttagta  35280 

caacctggag gtatggttaa tgtgcaggaa aaaagctcca tataagccta atccctatat  35340 

ataaaaaatc acggaattcc acagttttga acattttttt ttctttttga gacagagtct  35400 

tgctctgtcg cccagcctgg agtgcagtgg tgcaatcttg gctcactgca gctctctacc  35460 

tcctgggccc aagcagtcct tccacctcag cctcctgagt agctgggacc agaggtgtgt  35520 

actaccacat ccggctgatt ttttgtattt tctacagaga caaagcatcc ccatgttgct  35580 

caggctggtc tcgaactcct gggctaaagt gatccttctg cctgggcctc ccaaagtgct  35640 

gggattaaag ggatgagcca ccacacctgg ccaacacttt ttttgtgtgt gtggtaaaat  35700 

acatacaaca taaaagttat aattttaacc attttttaag tgtgtagttc agtgacatca  35760 

actatatgta cattattggg caaccatcac cactattcat ttccaggcag atagttaata  35820 

ctcatttttt tgtggtttct atatttgcaa atttacctgt tcgaaaaaat ttatttgtaa  35880 

cacccaaatc agtacagcgc tttggtaatc cttttcggac atatgcagaa cggtgaaaaa  35940 

atatgcacat ccctagttga ggttcaacaa ggggacactt tgctttcttt ttttcagtct  36000 

ttgtgccgta aaccagtgtc ttttttgtga tctatttaat gccttttttt tcatttttgt  36060 

actttttgtt gatgattttg ccatttaaaa tgggccccaa gcatagtgct gaagtgctgt  36120 

ctagtcttcc taacgcaccc ttgagtgaaa cttacctaac acctgcattt tctttgtaag  36180 

gcacatcata gccttgccat ggataaaact ctggacagtt gagtttttcc ttgcactgca  36240 

catggctatg gtgctttaca aagaagatgc acgtgttaga agtttcactc aagtgtgcgt  36300 

tacagtgctg tggctgtgaa ttcagtgtta accaatcata tatagtaaag aaggtgttct  36360 

taaacagaca cacacataaa acaaacttat gtattaatct gctgttgcaa aatgttgtga  36420 

ccagaggctt gcagaaacct aacccccaga agcaatgatt tcgtattcac taattcagtg  36480 

agcacagtaa ctgcatagaa tgaacaatga gaattgactg tagctccttt tttgaaagaa  36540 

gaggcttaat tatggagcaa ggcatcagga aaaatcacag gctttcctca tttgtgtgat  36600 

ttttttattt tgttcatgtc ttcaagagtg gagccctaag aagaaagctg agagctccca  36660 

gtaaaggggt gacgagtgcc tggcttagcc tcatagaggc cagaggaacg tcggtcttta  36720 

cactgggaca ttccacacac gcaacacaga gttattttct atggacagtt gagtttttcc  36780 

ttttccaagc atattctagg gttgtctttc tgtgccctgc tacatgttcc actgtactgc  36840 

tgtcagattt ttatctccca gaaattcttt gaagtcactt gtcttctggt ggcagccctt  36900 

cccttctctt ggccattctt tgtcatttgg tctttgttct tcagtgggcc tatcaggtgg  36960 

caggacagag aaatgcatgt gatcaatatg ccatctttaa ccaatgtcct cattatggtt  37020 

atgaaaataa cttttcatgt aattattttt attcaagtta catattacac acagtttaaa  37080 

gagtcaagac ttgttaaaaa agagtcccct agactcactg gtttccttgt ctcccaggat  37140 

ggccactttt aatcttttaa agtgattctt tagtctttta aatgattctt tcatacttta  37200 

taacatgctt gtagtcttac ttgtttttca ggtttaggca ttatctattg acattttatt  37260 

taaagtcatc attgacttta aaaacacaaa aactctttac tgaaatgtaa cacaggttgg  37320 

gtgcaatggc tcatgcctgt gaatcccagc actttgggaa gccgaggcag gcagatcacc  37380 

tgaagtcagg ggttcaagac cagcctgacc aatatggtga aaccctgtct ctactaaaaa  37440 

tacaaaaatt agctgggcat ggtgtgtgtg cctgtagtcc cagctacttg agaggctgag  37500 

acaggagaat tgcttgaacc caggaggtgg aggttgcagt gagccaagat cgcgcgactg  37560 

cactccagcc tgggcgatag agcaagactc catttcaaaa acaaaacaaa aagaaacgta  37620 

acatacataa aaagtgccca aatcataagt gtacagcttg atgaattatc acaaagtaaa  37680 

cacatttgaa taaccatgac ccgggcaaaa aatatactgt gacccacacc ctagaagcct  37740 

ccctttggcc tccttcaaat cccttcacta ccccacctcc tcaagtgaac cactgtgcca  37800 

ccttctaata ccataggttt tgtctgtttg ttgttttaac attgtactaa tagaatgtta  37860 

gagtatttta ataatagtgt attattttgt gtctatttct tttactctac ttcatgcttg  37920 

tgatattctt ccatgttgag gttttcattt gtaaccaact gttgtagttg tttgacttgg  37980 

cctccatttg ctatggattg aatcgtatgc ctcaaaattc atatgtgtaa gccctaaccc  38040 

ccagtgtgac tgtatttggt gatagggtct ttatagaagg ttaagtgaag tcgtagtatg  38100 

aatcctgatt gatagggtta gtgttattac atgaagagac accagaacgc tagctttttc  38160 

taccacatga gaacgcaggg agagggtggc catctgcaag ccaggaagaa ggtcccctcc  38220 

agaactgtga gaaaataaat tactgttaag tcccccagtg tgtggtattt tggttatggc  38280 

agtccaagat gactaatgca tcattcttca ggccactcta tccccctaga ggacttgcag  38340 

tctttttttt ttttttgcct cctcttttac tgactgagaa tgttgttaac actttcagaa  38400 

acagggtgtt aggatctttt gaccgttggt gaaccaacag aaagtggaag ataaggattt  38460 

ttctccagtg ggtgtttgct gtggatttgt tgggagaagc ccatctcatg tatgagctgt  38520 

cccatcccta ttttgtaata ttccactttg ctgctggcat cagagtgaat gtaaatggaa  38580 

tttcccagaa atttccacag caagtggctt tctcacttag tgagccccct tggtgtttgt  38640 

tgagtctccc tttacccaac cccacaatca ctggaataaa ggggtggtct tctctccagt  38700 

ctacaccttt ctgaggcact gcaatcgggg ataccccagt taccacctct tttggtgacc  38760 

ccaaggtttc agctttgcct gagctctcca ggctccagct ctgggccaag gtgattttgg  38820 

tggagtcatc ccagcgggga gctaggagga agaggggatt aggaactccc gctcaggctt  38880 

ccttgctgca cgtacacatg tcacatcaaa tgatggtgtt tcactctggg gacatagttg  38940 

cttttgataa aatgactttt ctgcagtttg gttaagctga atgaaacata tttgagctcc  39000 

tatttttgct tcagaggcta ttgaatagca gtacctgaag atgaaagtgt ataagaacag  39060 

aatcagtccg ggcgcgatgg ctcatgcctg taattccagc actttgggag gccgaggcgg  39120 

gtggatcacc tgaggtcagg agttcaagac cagcctggcc aacatggcaa aaccctgtct  39180 

ctactaaaaa aatacaaaaa ttagctgggt gtggtggcac gtgcctgtaa tcccagctac  39240 

ttgggggagg ccaaggcacg agaattgctc gaacccggga ggcggaggtt gcagtgagcc  39300 

aagatcacgc cactgcactc cagcctgggt gacagagcga gaccctgtct caagagaaaa  39360 

aaaaaacgca gaatcagaat ctttggaata gtgaccggat gccgtggctc atgcctgtaa  39420 

tcctagcact tcgggaggct gaggtgggca gatcgcttga gcccaggagt ttgagaccag  39480 

cctgggtaac ataaggagac ctcatttcta caaaaaatta gctggacatg gtggcacgtg  39540 

cctatagttc catctactcg ggaggctgag gtgggatgat cacctgaacc tgcggaagtc  39600 

gaggctgcaa tgaactgtga tcatgtcact gcactccacc ctggacaaca gaatgagacc  39660 

tcgtctcaaa aaaaaaaaac aaaaaaaaga atctttagaa taggaggagg atattgagca  39720 

gaaccataag aaactagtga ttaagagtcc aggtgtgaaa atagaaacca cgtctcagaa  39780 

gctcagagag aagaagaact ggaaaggcag catctttgat ggatttggcc atgaagagga  39840 

ggaggaataa agcagaatgg aggccagaaa agagtgtgta tgtctaacgg tttcattgga  39900 

attgggagat ctaggtatac catgtaaaat tacttatgaa ggtaaagttt gaagaaaatt  39960 

cattcgactt tgatttatat aatttttaaa acctcattat ctgttaaaac accagaagcc  40020 

ctgttttttg gttactgatt atgagtgttc aaggcctcag atcaactcag catttattta  40080 

tttatttatt tttatttttt tgagagggag tctcgctgtc ttgccaggct ggagtgcagt  40140 

ggcatgatct cggctcactg caacctctac ctcccaaatt caagcaattc tcctgcctta  40200 

gcctcccgag tagctgggat tacaggccca tgccaccatg cccagctaat tttttgtatt  40260 

tttagtagag atggggtttc accatgttgg ccaggatggt ctttgtctcc tgacttcatg  40320 

atctgcctgc cttggcctcc caaagtgctg agactacagg cgtgagccac cacacctggc  40380 

ctatttattt attatttatt tatttattta tttatttatt tgatggagtc tcattttctc  40440 

gcccaggctg gagttcagtg gcaccatctt ggctcactat aacctccgtt tccaggtttc  40500 

aagtggttct cccgcctcag cctttcaagt agctggtggg attataggca tccgccacca  40560 

agctcagcta atttttgtat ttttagtaga gacggggttt caccatgttg gccaggctgg  40620 

tctcgaactc ctgacctcag gtgatccacc cacctcccaa agtgctggga ttacaggcat  40680 

gagccacctc acccggacaa ctcagtattt attgagtact ccttatgtgc cagttagggc  40740 

tataaagatg aataagatgt cttttcccca gttgagatat gcataagaca gttcgtgttt  40800 

gcctgtttca gtagtcagta ttttcttttg cttattcagt ttccactgaa acttatgttt  40860 

tccaaataca aaattagaat tccaactttg cgtttttcag gcgcacacac tcgttttccc  40920 

tccactcctt ccccagttct gatttgcttc ctcctgaaaa tgggggttat agcccatcca  40980 

ctccagggtc agaattgctg gataccttgt tgcagtgatt ttttctgtag ctcctctgga  41040 

ggttatagac tcatagggaa taaataatgt ggtcaggtgg aggctttaga ccaagttaag  41100 

cagggttttt aaaacatggt gttaatgtac ataatgcagc cattctcaaa agtatgacat  41160 

ggggagaccc ctggaggttt tctgagaccc ttttaaggag tctgccgagt caaaactatt  41220 

tttgtgatac tagtaaaaca tttgcttttt tcattctgtc tctcacaagt gtagagtgga  41280 

attttccaga ggttacatga tgtgtgatat cacaacagat tgaatgtaga agcttgtatg  41340 

aaaatttcat acaaatatat tatttgtgtt ataatgtgct tattgttatt ttgaaatcaa  41400 

ttgttaaata cttttttttt tttttttttt tacagtttct cagtttttat ttgtattttg  41460 

gtagatattc gttgatacaa cccacatttg ggggaatgag taatctttaa aagtgtaaaa  41520 

gggaccaaaa agtgtgagaa tgtttgatgt agagaaactc caagctcatt ccctggactt  41580 

tggctataga tgctttcttc aggggtgggt cttctgggcc tgtgtcctgc aggatgccca  41640 

gtaggaagca cagcctcttt gatcttatgg gggtgggctc atttgctgtt ttggagctca  41700 

ggtgcaaagc cgagttactt gatattccct ggtcatggca aagcctctct ccacttttct  41760 

tcccttctat tgtcacttcc attctttttc catagtccat agaaatcatt tttacgtgac  41820 

agtgatgagc tgaccagaag ctatagaagc tatagtactt cctatatcct aatgggtttt  41880 

aaaaacactg gctggggcat actcaccctt tctgaacaaa ggctgctagg tgaccctgct  41940 

gttgccgctc tgtatattca cttggttagc ccacagattg gtttggacct aattcccttt  42000 

ccttctttaa ctgcccaaag ggcttttcta tttaaaaaaa aaaaaaaaaa atttttaaag  42060 

ttttcagatt caatacccac ctatttgtat gcttacccat cccagagtca gctaaattta  42120 

aagtgtcagt aaattgtaaa gaaaagattt gctacattgc atatgttttt agaagtgctt  42180 

tctgtgtata atctctctct ctctctcttt ttttcttggt ttggaggaga ctttcccctt  42240 

gtctataagt aacttaaata taaaatgtta taacaatacg tttattagtt tgaagcccca  42300 

attttctttt ttttttttct tttaagtgaa aacaagttta taaaagaagt aaagaaacag  42360 

gccaggcgct gtggctcaca cgtgtaatcc tagcacattg ggaggccgag gcaggtggat  42420 

cacctggggt caggagttcg agaccagcct ggccaacatg gtgaaacccc atctctacta  42480 

aaaatacaaa attagccagt cgtggtggtg cgcacctgta atcccagcta ctccagaggc  42540 

tgagggagta gaaactatga aaacttggga gatggaggtt gcaatgagcc gagatcatgt  42600 

cactgctctc cagcctaggc aacagaggga gactgtttca aaaaaaaaaa aaaaagaaac  42660 

aaaagaatgg ctgctccata gacagagcag cagtatcagc tgcttgactg agtctactta  42720 

tagttatttc ttgattatat gctaaacaag gggtgaatta ttcatgagct ttctgggaaa  42780 

agggcagaga tttcctggaa ctgaaggtcc ctcccctttt aggggactat ttagggtaac  42840 

ttcccaaggt tgccgtggca tttgtaaact gtcatggtgg tggtgggagt gtcttttagc  42900 

atgctgatgc attataatta gcttataatg agcagtgagg acaaccagag gtcactttca  42960 

tcgccatctt ggttttggtg ggttttggcc tgcttcttta ccacatcctg ttctatcagc  43020 

agggtctttg tgacctgtat cttctgccaa gctcctccta tctcaccctg tgactaagaa  43080 

tgcctgactt cctgggaatg cagcccagta ggtctcaggc ttattttacc cagccccttt  43140 

tcaagatgga gttgctctgg ttcaaacact tctgacatat ttcccccctc ccttttacag  43200 

ggggaccctt aatccttaag aattgtagcg ggacaaagat catctgtaac ttcttcaagc  43260 

caaatagggg tgatgatatt cctgcctatt agggtctctt gtatttaggg tagggagaag  43320 

tttagttaga aagcattgtt atagaagccc ttattttcag ttacacaatt ttataaagtt  43380 

acaattgctt attgtaacca gctgagtttt aggttttgtg gtttgttgct tgcttgcttg  43440 

cttgcttctt aatgccatat atcttggcat ttatcagtcc ataattacta aattcttaaa  43500 

atccataaat atttattatt ctttctaggt tgcaataaaa ataattgaca aaactcagtt  43560 

gaatccaaca agtctacaaa aggtaagatt ggttcaatgt ctagtacttt ttaaaaaatt  43620 

atcggtgcta attgccatct aatttgtccc ttaaataccc caactgttat tttatgttta  43680 

atgccataaa gcttcctatt cctcaaatga atgcaactta atgtagtatt tcatgaaaaa  43740 

ttgttgggtt atctttggtc ggagattatt tttaaatgtt cttaacagca caaactaaag  43800 

gctgtgcttt ttttttgtac ttttttattg atatagttgt acgaggctgt actttttatt  43860 

gaatattctt aatattgact agagtttttt taaaaataat acagtacaaa aatattttca  43920 

tgtaattgat attgtgcaaa tttgtacctt atagctaata ctgaaaattt taaagtgaac  43980 

actttggctt ccttaaactc ttgacacacc acatctgatt aaggactgat gattaatata  44040 

aaagggaaat gttaaagtaa aactgaaagt ggaaaagcat gttcataaag cagtattgcc  44100 

attagtatca tttaacatag atcaagtctt tgccctagtg ccttttagaa tcacctgggc  44160 

agatttttga aagtcttaac acttacataa taatgcctaa gcaattaggt tgggcccagg  44220 

cataggtatt tcagtggtag gacatcagca aataattaat gatcttcata ataaaatcct  44280 

tctagttgtt tttagcttcg cagagtcttt ttacatactt catttgattt ctagatttga  44340 

cctgtagtag ttgagggggg tacagagacc atgaagtagg aacaggaagt actgaatttc  44400 

agtcctggct ctgccactta gccgaatatc tgaccttgag caaggcactt aactttgctg  44460 

gaccttgggt ttctcatctt taaaatggag ataatttcat cttcttatga tggatgtgag  44520 

tattaatgaa ataatgcata taaaagggct ttgtaaactg cacagcactg cacagttgtg  44580 

cgatattttg ataagagcag tgctctatat acatttctaa tgtattcctc atggttattt  44640 

atatcctggt aattttgaag ccctgtccct gttttgtgtt tgggaggtgg ggagggagat  44700 

agactttctc tgcactaaaa atgttatttc aacaagtggt tctttgtgat ctgcaaccca  44760 

taatgggcct taaggcttct caaggtgggc atgaaacatc taaaaattcc agtcctttgt  44820 

cctgaagagt aaattttatc tatttcctta aacttccata tcttcagcta tctaaggatt  44880 

tggtactaat aaatacatta gagtttaata caatgtggta ttcagaacta aaattaacat  44940 

acaaggatgt ttaatgagga ctctaattga gtattctatg atgttacata ccttccacta  45000 

ttcatgtgta cctggatata attgtaatcc taacagtttt cccggaaaaa tttttaccat  45060 

ggtgttgtat caagttggct gcagtttttc cttcttgttt gcttgcttcc tttagtcatt  45120 

ttttatttta ttttattttt ttggtaatga tttttcattg ctgctcttcg tttattattt  45180 

gtcacatcat tatcagttta gtgcatggta gtttggttag cccattagtg tgattatgca  45240 

tatttgcatc tgaattaatt ttgacttata ataataatta aaactttaag atttgttttt  45300 

ggtattattc aagtatgaac cattcactga agacttattc taaagccagc tctatcccaa  45360 

gttaaataac ttgataagta taatattttc agtttatagg ccattgttta aaattgtgta  45420 

tataacttca tatgcttatg aagtaaatta gaagcatttt acatacattt gtttccaatt  45480 

ctttttcacc aagtatctta tccccagccc ccccatcttc ccccaccccc agcaattttg  45540 

caacaatgta gaatgtacca ggcaactttg tcagccccct ttgcagtcat tcttgcatcc  45600 

ttttttcttc tcagcaccat tcatagttgt atcacacttg cttcaggaac agctctctta  45660 

gatagtgatt taaagctgtg gagcatgccc tagcagctaa cattcatcat aaggaacatt  45720 

ctgccatcag cagtgtgcaa tctctttttt accaccacta ccgaaaaagg tggactggct  45780 

cattcaggca gtattttaac agtgaacaca cgtgttaaaa tatcggtttc atgatattca  45840 

ggcttgcata ctgggtcatg aacatttact aaatgcacat ataagtaaac ctgagttgac  45900 

tatgtttgca aattgatatt attttcacag atgagtctct tcatttttcc tttgtatttt  45960 

tgcagccatt gaattaataa acgttagatt ctggtgagag atttattttt ctccattgtt  46020 

ttttaagaga tgggtcttgc tctgttgtcc aggctggact cgaactcctg ggcttaagca  46080 

gtccttccac tttagcctcc caagtagctg ggactacaaa tgcacaccac agcatctggc  46140 

tatatacctt ccaatgtctc actagtatat ctggaatact attctattct tacgcatctt  46200 

ttaggtcaat tttttgtttg ttcgtttgtt tttgtttttg tttttttgag atggagtctc  46260 

gctctgttgc ccaggctgga gtgcagtagt gggatctgag ttcactgcag tctccctctg  46320 

cctcttgggt tcaagcaatt cttctccctc agcctcccaa gtggctagga ctacaggtgt  46380 

acgccaccac acctggctaa tgtttgtatt tttagtacag atgggggatt tgccatgtta  46440 

gccaggctgg tctggtctca aactcctgac ctcaggtgat ccacctgcct cagcctccac  46500 

ttgctgggat tacacgtgtg agccaccatg cccaggccaa ggtgtgtgga tcacttgagg  46560 

tcaggagttc gagaccagcc tggtcaacat ggtgaaaccg cgtctctact aaaaatacaa  46620 

aaattagctg ggcgtggtgg cacatgctta taatcccagc ttctcaggag gctgaggcag  46680 

gagaattgct tgaacccagg aggcgacaga acaagacttt gtctcaaaaa aaaacaagaa  46740 

atttgtaaca tgtaatgaaa taattgattt tttgtaatgt atttatgata gctggttagt  46800 

tagccaacct tgagcacatt cagggatgga gacacactcc ttcccgtagc atcttgttcc  46860 

agtgttcagt ggctttgcta ttagagcctt ttccccttac ttcagactag catctgtctt  46920 

ctagaaactt ctacaacact gtttaccatt tgtcatatgg agttatagtt actccaaaca  46980 

taaccagccc ttagaagttg ctattttggg tcttgttgat tttctcttat gcagagtaaa  47040 

tcccctcagc ctccttgggt actcccacag gagtttcgct gaacagaagc ctactttatt  47100 

ccatacttgg aattgtttcc cccctcccac ctgaatttgt ttgattcctg ctaaaattca  47160 

tttaattgat tttctgcctt aattccagtc ttttggggga ttttggaata atgggtcatt  47220 

tgtattagct gctatgtaaa ttagatatgg atgtctccat ccaattaaaa tattaaacaa  47280 

gacaagaaca agacttttca atggagaatt catccaagtt gatactgctg acccagtagt  47340 

aaagcatttt ttgagtaaga tttaaccacc attcttaaat ctagactgag taggacagaa  47400 

agggaaatcc ctgtgttttt aaattttaat gagatttaca gaggaagaaa aaaaggaaca  47460 

ttaaacacaa atatatgcaa aatacccagt aggatttatt aaagcattat tgactatgga  47520 

tttcatcagg gtctttgtgg ggaaatcctg cttataccca cctcaatctt cctccctccc  47580 

ttccttccac tggccttatc gtgattgtaa aatagggcaa cactacattc cataaaatag  47640 

aataagtgtc cctatgagct gagcagaagt tggctttaga gacaggcaaa ggctgaagaa  47700 

ggctgaggca ggcccggcac agtggctcac tcctgtaatc ccagcacttg gggagcctga  47760 

ggcgagagga tcactcgagc tcaggaattc gagatcagcc taggcagcac agagagaccc  47820 

gtctctacca aaaaaaaaat taaataaatt aaccaggtgt ggtggtgtgt acctgtagtt  47880 

ccagctactt aggaggctaa gatgggagga tcacttgagc ctagaagttg gaggctgcag  47940 

tgagctgtga tggtgcccct gcattccagc ctgggcaaca gagcaagacc ctgtctcaaa  48000 

aaaaagctga agcaaagaac aaagagtgta ttggtccttt cagaattcct tttttttgta  48060 

aggcagggac agggaaacag aacaatagac cacaatagac tataccacat agaaaagtaa  48120 

ccgattagtt aatgtcaggt tacttcacac tacatttttt tctgtaagga ttaaagcagt  48180 

aggaactttg ttattgtgcc aattgaagtt ttttcttttc ttttcttttc ttttcttttt  48240 

tttttgagac agagtcttgc cctgtgaccc aggctggagt gcagtggtgt gattttggct  48300 

cactgcaacc tctgcctccc gggttcaaga gatacttctg cctcagcccc ctgagtagct  48360 

gggactacag gtgtgtgcca ccacgcctgg ctaatttttg tatttttagt agagacaggg  48420 

tttcaccatg ttggtcagac tggtctccca actcctggcc tcaggtgatc tgcctgcctc  48480 

agcctcccaa agtgctggga ttactggcct gagccaccgt gctcagccag gacagtttaa  48540 

atcttcaatc aggggctgga cgcagtggca cacgccaata atggcagtac tttgggaggc  48600 

cgaggcgggt ggatcacctg aggccagggg ttcgagacca gcctagccag catggtgaaa  48660 

ctgcatctct actaaaaata caaaaattag ttgggcgtgg tgacataccc cagctaccca  48720 

gtaggctgag gcacaagaat cgcttgaacc tcggaggcgg aggttgcagt gagccgagat  48780 

cacaccactg cactccagcc tgggtgacgg tgagactctg cctcaaaaaa taaataaata  48840 

ataaactgtc ctgtttggga aattagctgt tatctccttt tcttctgatt tctaggaagg  48900 

tcagataaca acttaattta ggtttgggaa tgtggaatct tagcagggat tactccattt  48960 

ttaattttaa cctggtttcc tggggcctaa tgcaggagtt tagtcccaaa caatggcttc  49020 

ctataatttt tatttaacaa ttcttccctt ttggtcaggc tttcacctag gtaagagtgt  49080 

aaccaaaacc taggatatcc ctgctgttct cagttgccat cattttgagt ttcccgtttc  49140 

agcatgccgt tgacagggtg ttctcattat cgtgtgtttc ttttgagttt ttgttgttct  49200 

agccagagag aaccatttga catctgatag gtggctacat ggagacactt aacactctgg  49260 

gaggatacag cgtaccagag agactaccat tatgactatc atgaggatca caccaagcat  49320 

ttagagtatg ctcctaagcc agggttttta tgaaccaaat caactaaaat tgtatagcca  49380 

aacaaggagt ctgccaattt taaccaagtt gtccgctcta ccatacccaa atcgcaacga  49440 

gaagtgtcat gaactgcaca gattcctcca tgtttagtag gcatcccagc attccgtgac  49500 

cgggctaagt ataaagcagg gagtgcaagt tacccacaga agctactgac tgtgaaattt  49560 

tagctacagc atgatcctgc caaactgaaa gaggtaggca ttagtaagga aaaattaaga  49620 

ggggcaaaag cattgttatg aagtcttgtt attatgacag tcttgggaaa agctgtccat  49680 

agcatgcagt ccacaacttc tcgtcctggt tcgcagtttg aatgtctctg gttgtggcat  49740 

ctggcattct ggtgaattct ctgtgtggcc tacacatcag gcatgagact cgaaatttac  49800 

atcaagctgt cagctttggt ttatagggct tctgaaattg agcagctcat tcttcattgg  49860 

caagttgtag ccagatatta aagaaaacta gaagaattca gaatctagtt cagtcaggaa  49920 

taatcttatc aggtcatttc tggaagtcaa ttctgtgaat taatatttta gcagcgtttt  49980 

ttgcttctaa tttcaaattg gaaggtatag ggttattcat tgtgcccctc aagcctggtc  50040 

cactccgata cccctcaagc accagacacc tacccaggaa gagggaggct gttttctttt  50100 

taaagctagt atttgctttg gagccactgt tagtgcttag agctctgtag cagtagcagt  50160 

agtggccttt tttggcgtcc tagggaatct tggtcatggg atgtagcagg gaaacttata  50220 

atttgaaagc aaggagaacc agttcatgct tttcatgtgg tctgtcgtgt aatgactttt  50280 

actgctgcca ccactgggtt attttgggca ctgttgattt agttttctta agccagtact  50340 

tttcaaccct tcttgtgcat tagaaacatt tgtggagttt gaaaaaagca tatttccttc  50400 

acagtacttt cctccctaga ggtcctatct tggcgggtct agaaatgtgg tgatctcagt  50460 

acacacccca gatgagaatg gctcctagtc tgtcttcact tcccccaaag ttcttaattt  50520 

ctctcttctt ccaattttac ttatttttat ttatttattt atttttttga gacggagtct  50580 

cgctctgtca cccaggctgg agtgcagtgg tgcgatctca gctcactgca agctctgcct  50640 

cctgggttca cgccattctc ctgcctcagc ctcccgagta gctgggacta caagcacccg  50700 

ccaccacgcc cggctaattt tttgtatttt tagtagagat ggggtttcac cgtgttagcc  50760 

aggatggtct caatctcctg acctcatgat ctgcccgcct tggcctccca aagtgctggg  50820 

attacaggcg tgagccacca cgcccggcct atttattttt tattgattga gtgattgatt  50880 

gatggggtct tgtcctgttg cccaggatgg aaggtagcag caagaccaga gctcactgca  50940 

gcctggaatt cctgggctca agtatctttc cacctcagcc tcctgaggta gctgggacta  51000 

taggcgcgca ccaccacacc caactaaagt aacctatttt atttatttat gagacggagt  51060 

ctccctctgt tggccagcct ggagtgcagt ggtgccatct cggctcactg caacccctgc  51120 

ctcccgagtt caagtgattc tcctgcctca gcctcccaag tagctgggat tacaggcacc  51180 

cgctgccaca cccagctaat ttttgtattt ttagtagaga cagggtttca ccgtgttagc  51240 

caggctggtc tcgaactcct gacctcaagt gatccacccg cttcagcctc ccaaagtgct  51300 

gaattacagg tgtggccacc gtgcccggca aagtaaccta ttttaaagat gaccccttcc  51360 

ccaaatattc taagtttcat agacagctgc tactgccact gccactgctg aatattttct  51420 

ccctctctgg aactcttcct aggaatgcct tagtacccag ttcctggcct cctttctcta  51480 

ttgggtgaag cacaagttat tttggaaatc cttttcattg aacaactctt ttcatctttt  51540 

tcttttcttt cttttttttt tttttccaac tatctttctc tttcattttc ttatattgac  51600 

ttttcaggcc attaacaaaa gtagtaacca ctgtaaaaat agttgttaca gtcttgtctg  51660 

ttatttaaaa tccagtgtct gcattcacat cagtgtcata aatctgataa attaatacaa  51720 

ataggagatg gcaaatgaaa tccaagacag gcacttctta tattgattga ttgaggctgg  51780 

gtcttacttt gtagcccaag ctgaagtgca gtgtcatgat catagctcac tgtagcctgg  51840 

aacttctggg cttaagcaat cctcccgtct tggcctccca aagccttggg attataggca  51900 

tgagtcacca cccccagcct gattatacat atttaaaata ttgagaatag actgggcacg  51960 

gtggctcact cctgtaatcc cagcactttg ggaggcccag ctgggtggga tcacctgagg  52020 

tctggaattc gagactagcc tgacgaacat ggtgaaaccc cgtctctact aaaaatacaa  52080 

aaaaattagc caggtgtggt ggcgcatgcc tgtaatccca gctacttggg aggctaaggc  52140 

aggagaatca cttgaaccca ggagacggag gttgcagtga gccaagatgg caccactgca  52200 

ctccagcctg ggcaacaaat gagaaactct gccaaaaaaa aaaaaaattg agaataaaac  52260 

tgtatatatg tttgtttatt tttagatttc aaaagagaag aaatagaaaa accggctttc  52320 

agtattgttg cttctttatt ccttataaac ttttaaattt cttgccagac ttatttttgt  52380 

tttggcaata aataatacgg gttgatattt agaatacatt ataaactcgg gaagctgagg  52440 

caggaaaatg gtgtgaacct gggaggcgga gcttgcagtg agccgagatc acgccactgc  52500 

actccatcct gggcgacaga gtgagactcc gtctcaaaaa aaaaaaatac attataaact  52560 

gagaatagta gagtgtattt tagagattga ttgtttgttt ttagaattga ggtctcacta  52620 

tcttgcccaa gctggtctca gactcctggg ttcaagcatc ctccttccga ggattccaat  52680 

ctgccttcca aggagctggg attacaggca cacaccacca tacccagcta aagtatattt  52740 

ttcattgtac caaggactta ttatgctatt ttagaaaagt caccaaggaa ccaagtattt  52800 

taagtgggtt aaacttagag catagcctgg acccatttgc agaaaatata aacttgggtg  52860 

caaattaggc ctttgtgaga gaattataac agtaacatca gccagaatca caaacacatg  52920 

tcaggagttt attgtgtgcc aggtgctgtt ccatgcactc tgtatgtcaa gccatccttt  52980 

cattgtagag gtgacagggt cagggaggtc aagttaccta gacttagtga gtggtacagc  53040 

tgggttggga ttaggtagta tagctcctgg aatcaaattc tacacacact ttatcttata  53100 

gcattgcatg tacttttcac aacagtcctg tgaagcagtt gttttctttt tttttctttg  53160 

agacagagtt ttgctcttgt tgcccaggct ggagtgcaat ggcgtgatct cggctaaccg  53220 

caacctccac ctccctggtt caagtgattc ccctccctca gcctcccgag tagctgggat  53280 

tacaggcacc cgccaccacg cccagctaat ttttttgtat ttttagtaga gacagggttt  53340 

ctccatgttg gtcaggctgg tctggaactc ccgacctcag gtgatccacc tgcctcagct  53400 

tcccaaagtg ctgggattac aggcgtgagc caccacgcca ggccgaagta gctgttttca  53460 

aaatctatct tataggtaag taggttaaag ctctcaagat tttgtggttt gttcactcat  53520 

ccagtgaata agggactgaa ctagccttag aacctaaatt tataacatca aatagctttc  53580 

tttgcataag ttcccttgga gccagtcact catagtactt tccatatggg aaggataaca  53640 

aaggaacata tggaaattca gcttgcatgt ggtagatacc tagtaaaatc tgataagtta  53700 

attttgttag taccaaattc attttaacac taaattaatt tttcctgatg ttgctctgat  53760 

tctaggaatc ttgaccacca gaaccttgag tttgggagat gggaagattc ttagtttgtc  53820 

tttgaaatat ttgatcataa aaaacacatt attggccagg catggtggct caagcctgta  53880 

atcccagcac tttgggtgac caaggcaggc agattgctga gctcaggagt tcaagaccag  53940 

cctgggcaac atggcaaaac cctgtctcta catacagaaa ttagccagat gtggtggtgc  54000 

gcacctgtag tcctagctac ttagggggct gaggctggag gattgcttga gcccgggagg  54060 

tcgaggctgc agtgaaccat gttcatgcca ctgcattcca gcttgggtga cagagcaaga  54120 

ctccttctct aattaaaaaa aaaaaaaagc acacacattg ttgctactct tattttacat  54180 

ttttagaaaa ctgatttgtt gtattactca gctaaagcta agcaattttt taaaatttag  54240 

tttttaattt ttattaaata ctgactgcat acaaaagaat gttccatgtt tagcatataa  54300 

atatgtatat gagatgagca cccttatact acctgcttca agaaatagat cttcaaccat  54360 

acctttaaac cagtcccata ttgtgcccct cctcaacctg attccccttc ttcattgccc  54420 

acctactggg taaacactaa caaggatttt gtgttattat tttcttgctt tgtccgtgta  54480 

attttaccac atatggatca ctcatcaatg tagtgtaaag gttttttttg gtctgttttt  54540 

tgtttctttt gtgtttgttt gtttgtttgt gactgagtct cgcactgtct cccaggctgg  54600 

agtgcagtag tgcgatctca gctcactgta acctctgcct cccaagttca agcgattctt  54660 

gtgcctcagc ctcctgagta gcagggatta caggcgtgcg ccaccacacc cagctaattt  54720 

ttgtattttt agtagagacc aggtttcacc atgttggcca ggccggtctt gaactcctga  54780 

cctcaagtga tccacccacc tcagcctccc aaagtgctgg aattacaggc gtgagccacc  54840 

gcaccccacc aatgtagtgt aaagtttaaa aaattgtata aatggactca tgctatgtgt  54900 

attctcctat tggcttttgc tttgcttcct tttttttgtt tttttgagac ggagtttcgc  54960 

tcttgttacc caggctggag tacagtggcg tgatctcagc actgcagcct ctgcctcctg  55020 

gattcaagtg attctcctgc ctcagcttcc aaagtatctg ggattacagg tgtgcaccac  55080 

cacacccagc taatctttgt gtttttagta gagacgggtt ttcaccacgt tggccaggct  55140 

ggtctcgaac tcctgacttc aagtgatcca cccacctcag cttcccagag tgctgggatt  55200 

acaggtgtga accaccatgc ccagccgctt ttgctttctt ttacctacat tgtgttccat  55260 

gttgatgtat tttgctgtaa ttcaccttca ctgctatgtc cattttcaag aatatgtagt  55320 

atcccattat gtgaatatgc cactctgtat ttattctgtg attcagagac atttggattg  55380 

ctttttgtat tgcaaacatg actgctgtga attgtcctct gtgtgtcctg gcacacttgt  55440 

gaagagtttc ttaaatatat atacttagaa ttcttgtatc acagagtctg tctgcacatc  55500 

ctccttcttc attagagaag gccaaattat tttcagagca ggtatgctaa tttatatttc  55560 

catcagtagt gtgtaagaga gcacaagtaa tgtagcatcc tcatcaaaat ttgattttct  55620 

ctgatttttt aaaatttgtg ccatcacagg agaattgctt gaacccggga ggtggaggtt  55680 

gcagtgagct gagattgcgc cactgcactc cagcctggcg acagagcaag actgcatctc  55740 

aaaaaaacaa aaaaattgtg ctatcaattt ggtaaatata aaagtgatat ttggccaggc  55800 

atagtggctt cctccttaaa ttccagcact ttgggagcct gagatgggaa gatctctcca  55860 

agccaggagt tcaagaacca gcctgggcaa cagagcaaga ctctgtatct acaaaaagat  55920 

tttttttttt tttaattatc tgggcatggt ggcacatagc tgtggtctca gataattggg  55980 

aggctgagga ttgattaagc ccaggagttt acagctgcgg tgagctgtga ttgcaccact  56040 

gcactccagc cagggtaaca gagcaggagc ccctcttaaa aaaaaaaaaa gaaaagaaaa  56100 

gaaaaatctc attatggttt taatgtaaca ttttcctaat tactgatgag gtcatgcatt  56160 

ttttcatatt taggtttttt gtttcttctg tgaagtacgt attcatcttt tgtttaattt  56220 

ctagtggatt ttttcttagt tattttagga tatcattata tatcatggat actattatat  56280 

atgtggcaca caccttctac ttgatggtat atcttcactc tcttgatact gtctctcagt  56340 

gaatagcaga ggctcctaat tttaaagcag ttacatttat cagtcttttt ttaatatgct  56400 

ttgcactttt tatgtctttt ttgttttttt gtttttttgt ttttgagacg gagtttcgct  56460 

ctgtcaccca ggctggggtg cagtggcacg atctcggctc actgcaagct tcgcctcccg  56520 

ggttcacgcc attctcctgc ctcagcctcc cgagtagctg ggactacagg tgcctgccat  56580 

cacgcctggc taattttttt tgtattttta gtagagacgg ggtttcaccg tgttatccag  56640 

gatggtctcg atctcctgac ctcgtgatcc acccatcttg gcttcccaaa gtgctggaat  56700 

tacaggtgtg agcccccacg tccggccttt tttgtgtctt ctttaagaaa ttcttctcta  56760 

cctggggtca taaacatatt tttctctgtt gtcttcacat gtttaaagta atctttaagc  56820 

caccagcagt catgtgttac gaggtaggga tccagtttca tggtttttcg tatgtataat  56880 

cacttgctgc ctcacctctc ctttctttgc tgatctgcat cgtggacaga gtctccgtgt  56940 

ctaaacacac actttgttct tcagaagtgg ttattctggt tcacttaaca attgccattt  57000 

gaaaagcaat tatttttatt ttattttcat atttttaaat tttattttta atgataggac  57060 

accaaatgat aaccagaacc ccaaaataca taggtgaaaa tctgagctaa attaatagaa  57120 

acacaggcat gacagagaag actttatcac ttaactctct taggccattc attaattaca  57180 

cagtaagtag ggggaaaagg tacatatctt aatatacagc acctccatgg ccaggtgcgg  57240 

tggctcacac ctgtaatccc agcactttgg gaggctgagg tgggcggatc atgaggtcag  57300 

gagattgaga ccatcctggt gaacatggtg aagccccgtc tctactaaaa aatacaaaaa  57360 

aattagctgg gcgtggtggc gggtgcctgt agtcctagct actggggagg ctgaggcagg  57420 

agaatggtgt gaacccgggg ggcggagctt gcagtgagcg gacatcgtgc cactgcagtt  57480 

cagcctgggt gacagagtga gactccgtct caaaaaaaaa aaaataacag cacttccatt  57540 

agcccatagt atagctgttt taatcccctt ttcaggatac ataacagctg tgtgctagga  57600 

tattatcgtc ataactattc caatgtgtga tgactatgag gtatattatt ttctcagagt  57660 

tgggcaatac ataacatttg aataagccag actaacatct ttctaggcta tagttctaat  57720 

gtagagcaat aaaaatagaa ccaaacaaaa tatacaaaca tgtggaacct aaaacacaca  57780 

gaattcttgg atcaaagaaa aattgcaaac aaaaattaca gtatatctag gaattaatga  57840 

taataagctg tgtgtcagaa cctatgtaat actgcttttt ggtgctccgg gaaatttgta  57900 

gccttaaaca cattattaaa caagaatgac aaggaatgca ttaaacatta aactaatagt  57960 

ttagaaaagg gaacaaaata aatctcagga ataaataata atgtaaggag tcagtaaagc  58020 

taaaggcaga aaataatgaa tttgaaaaca gtagaaatgg taaatccaaa actttggtgg  58080 

gtgtcccccc ccctcccacc gacaaggaag tgagaagaga ggcaatgaaa tagataagct  58140 

actaagtgct gccaggggga agggagagaa aacacagaaa aatgaggggg aaataccaga  58200 

tactgaagaa tttaaattat tataaaggaa ccttttctgc aactctgaaa aatgttagaa  58260 

tatccaaaga aattgataat tttctaggaa aacatgactt accaaaatta actctagaaa  58320 

agaatcgata cacatcagta acaacagaag ttgagaaagt agttaacata ttgccaaacc  58380 

tggaattcat gattgaattc tttgagatct actgtgagta catactctgc ctctgttcag  58440 

ctgttccaga acttaagaag aggaacttcc aaattctttt ctcaaattca gaaacaatgc  58500 

tattgaaata tattggaaac aggaacgaaa actacagttc agtttcactt ataatatcca  58560 

ttctaaaatt gggaattaaa aatactagca tataggacta aatactggta catttatctt  58620 

tgtttcccca aagattcact aaatgatggt aacggaatta aaaaggaggg gaaaagagtc  58680 

caggaattga gtactgaggc attctcagga agagcaccaa gagagggagg agatacccag  58740 

cggtcacagt ggaagtcgtc tttgagactt agagcgtttg aggaaggggt cgtctttaaa  58800 

ataggttacc tacctagcac ttgggagacc agaccagcct gtggcaacca gtgacatcag  58860 

ttcctttgag tctttccaga gatactctgt atattaagaa gcaaattttt ttttcctttt  58920 

ttacacaaat gcattttctt gaaaattcct tctcatgaac tttgccagcc tctctgtctt  58980 

ggtttgtctg agagggcctt tgatgcactc ttccatttag gtgctgtggt agttgaggca  59040 

aagggacagt ttctgtagag tgatgaggga gtgacttagg tggcctggtc ttctgtccct  59100 

tatctgtgta tctggagaag ggagcctgaa caccttcatt gtgatggttt agatcagttt  59160 

tatgtctgta acccccgtgt tctcttttac atactcattt tactttcgta tcggttggta  59220 

aaattgtctt tttttttttt tttttttact agagactaaa attctctctc tctttttttt  59280 

ctacttgtca aaaggtaaaa ttttattttt ccagtggtaa tacttgacaa cccccaggtc  59340 

ttggctattg ggacatgttt ctttacttct ctgataccgt agatttagtg tccttgatat  59400 

ccccattgcc aggattccaa atctttgcct tcaaaggtat ttattctcct cttgtgtgcc  59460 

agttccatag aggatgtata gatgtgaaaa tgtgtggagg atatagattg atcagtaagg  59520 

agagaattct ttcaatttat acgtttccat gtaatttgat ttcttttttc caactaacat  59580 

ctatttaaga ttgaaaaggg aatgtggaga aataagttgt attaagatag tagaaatagg  59640 

ctgggcgcgg tggctcacgc ctgtaatccc agcactttgg gaggccgagg cgggcggatc  59700 

acgaggtcag gagatcgaga ccatcctggc taacatggtg aaaccccgtc tctactaaaa  59760 

atacaaaaat tagctggaca tgatggcggg cacctgtagt cccagctact aaggaggctg  59820 

aggcaggaga atggtgtgaa cctgggaggc ggagctttca gtgagccaag atggcgccac  59880 

tatactccag cctgggcgac agagcgagac tccatttcaa aaaaaaaaag tagaaataag  59940 

gtgagtttct cttatttaaa tggcctttta caattacaaa actttaaaat ttttctggta  60000 

tagtccttat agggactttc cttaaagttc acatttgcct ttcagtacat tattcctatc  60060 

caaatttaac tatctttggt catcagattc tgagattatg aagtctctgg catttttatc  60120 

tcacttgtat gcaaattgtc aacttcgtaa aaagctctgt gccagtaccc acctgttgct  60180 

ctggactttt ctatatcagc agcttataat ttgttgattt ttttttttag ttaaatttct  60240 

aaggtagcaa tgtggaatcc tgagatgaac gtagactttg gagtcaggca acccacaatg  60300 

agaatcctgg ctccagcata tattagctga gtctttggat gagtttccta acctgtctca  60360 

gtcgtctgtc tctgtatact ggagatgatc atactcagct gatagagttg tgaaaattaa  60420 

gcttagataa gactgtgaat gtgaagcatc tggctctatg cgtcagacac agcaggcact  60480 

agataactgt tagcttcctg cttcctccct gtcctgcttg tttaacttag cataaagctt  60540 

atttacacat ttgctgcctg ccagtatcta cctaatacat aattccaata gagaggtgaa  60600 

tacataaagt tatttgggct aatatcctgc cactacctct cttgggattc tttggctgct  60660 

ctttttgcct acggaattaa atttttacta gtcttctatc tggtcccatt tacctgtcct  60720 

ttttgttttc acattgcatc cctggtatga cctctgctgt aactcaggag ttctcgcatt  60780 

ttaatatggt gtctgcagaa tattagttat ccactgctgc ctaacaaatt cctccagaac  60840 

ttagcaactt aaagccaaat cttttgaatt cctgtaatag tccatctttt tcctgctttt  60900 

tggctctaat tcactttgtt tcatttctgc tgtactgtta gtagagactt aaaaatgatt  60960 

gccttcattt gacctgctcc cctgtcatca gaactgtgac aactctgtaa caagcattgt  61020 

gctgcggagg atttaaaagc tatgtggtca ttagaatgct gaggctggct cagaccgcag  61080 

ttgttggtag ttagtgcttt catgcaggca tttatcaaac aaatgcattt cagttgtgtg  61140 

ccagccttgg tttcaggtat acagtagtga aaggagacag gcatgctccc tgtgggtgac  61200 

acaaggataa caaacaggtg cacaaaaatg tgtcttcata gcttgaaaga catcccagga  61260 

aagaagtgaa cagatgggct atgatgtaaa acaaggagac ctacttagat acgttttcag  61320 

agaatctgcc tgagacttaa aggatgaaaa gggagaagac atttaaagga atttagtatg  61380 

ttctgtggcc aggcgcggtg gctcacatct gtaatcccag cactttggag gccaaggcag  61440 

acaaatcacc tgaggtcagg tgttcgagac cagcctggcc aacgtggcaa aaccccgtct  61500 

ctgctaaaaa tacaaaaatt agccaggcat ggtgggacct acaatcctag ctgctctgga  61560 

ggctgagaca gaagaatccc ttgaacctgg gaggcggagg ttgcagtgag ccgatattgt  61620 

gccactgcat tccagcctgg gcatcagagt aagactccgt ctcaaaaata aataaataaa  61680 

caaacagtat gttctagtaa ctaaaaggag ttggggtgac tagaacgtac ctttgagggg  61740 

tatgcagaag ttggcaggtt gcagggatgc catggccatg gtcagggttt cattctcagt  61800 

gctgtgtatc ctgagctata ttgatatggc atccaaagtg gagattgttg tctttttttt  61860 

tttttttttt tttttttgag ttggagtctt gctctgtcac ccaggctgga gtgcagtggc  61920 

atgatctcag ctcactgcaa cctccaggag gtgttgtaat ttagcagttg ggaagtaatt  61980 

gggagatttg aattctagct accaattcaa ctataatgga ttggaaaaca agatttctgt  62040 

gttagtttaa cagaggagag ctaaaaaaga actcaggcct gaatggttgt caggaattta  62100 

cttgggtgac tatcttctca tctcagaaca taaaatgtag gaattaccac agttgcaaag  62160 

ggagatgttt atgttggaga taaaaatgct cctcccttca aaaatgagac agtattttag  62220 

ataggaaagg ttatttatct gattacatgt tttaaaattc tgagcgtaag gttatatgtc  62280 

aaatcctgtc catgggctgg gcacagtggc ccacacctgt gatcctagca ctttggaagg  62340 

ctgaggggga ggattgattg agcccaggag gtcaaggcta cagtgaacta tgatcacacc  62400 

actgcacttc aacctgggca gcagagcgag accctgtctc aaaaaataaa aataaattaa  62460 

caaaaaaatc tggtccatgt ccatctcctc ttagctgcta attcaatttt agattagaca  62520 

cagtggacaa ggacaagtat ggtgagagtc ctgtgatttc tcaccagctt cctttccaca  62580 

taggccgctg cttctcttct tccaaggttt ttccccgctt ttgcctcctg gaggttgtat  62640 

cctgggtgtt aggagactgg gttccggaca cattccccac agaaggatag caggacctta  62700 

gaagatcttt ttctttcttt tcctggtttc ctcttgtttg caagagggtt gaataggatg  62760 

gtctctaaaa tcctgttgtt tttctgggtt atattaaccc aggccataat gataagaacc  62820 

tgctctgaat tcacaacatg tatttataca acagcaattt aatatttctt attctgtgga  62880 

atggctagga agctctgctg gtcttggttg gatggttttt tgtttgtttt tttttgagac  62940 

agggtctcgc tttgtcgccc aggctggagt gcagtgacgc catcagctct ctgcaacctc  63000 

cacttcccag gctcaagtga ttctcttgct cagcctcccg agtagctggg actacagaca  63060 

catgctactg cacccagcta atttctgtat ttttagtaga gatggggttt caccatgttg  63120 

cccaggctgg tctcgacctc ctgagctcaa gtgatccacc caccttggtt tcccaaagtg  63180 

ctgggattac aggtgtgagc caccgtgctc ggctggtttt tcttaaggtc tcacctgggt  63240 

tcacttgtgt ggctgaattc agctggtggt ttggcagggg ctggatgcag ttacaacaga  63300 

ggatctgtct ctttaaataa ctacccttca tccccaaaga ggccagacca gctccttcac  63360 

agtgctccaa gagagcaagc catgacgccc aagcatttta tccagcctct gcttgcttca  63420 

gtttgctaag gtcccactgg ccaaagcaga ttacatggcc aggtctaatg tcaatatgaa  63480 

gggggcactc cacaaaagcg tgaacatgta aggcatgact catgagggtc actaatgtaa  63540 

tagtcaccac aacctccatg ctaagttacc tatattctcc agtgaggatt tctcaaggtg  63600 

gttttgttca tagtcttcta atagaattat ttggaattat cagtttaata tgcttatgat  63660 

gtatttcact ggaaccatac aggttttgat tcgcagagtt gggagccctg ggtagatact  63720 

gaatcagact aagtttaatc acagaaatta ttcctgcgta agtctgatct tatgttttca  63780 

agatagcatt gtaaaattca gagtatgtta ccatccccct ttgagacctc tgctgttttt  63840 

aataaatgga agcatttggg aatactattt ggtaatagtt tattaaaact acttcagaga  63900 

tattctggac tttcatatta gtcttagata tggattaata aacattagca atgaatctgt  63960 

tatctaagag aaaaatttaa atttatatta caacagtgga atataatgtt taataacttg  64020 

tgttgggggg attatgtgtt ttgtttgttt ttttttttag ctcttcagag aagtaagaat  64080 

aatgaagatt ttaaatcatc ccaatatagg tactttctgc ttttttaaat attttggggt  64140 

ctaaatacgt acttgaaatt atgtcataaa gctaaacacg tattctagaa atggtagagt  64200 

acacttctag taaaatatat atacaagttg ttgatcattt gtattagctt tttgaaattg  64260 

ctgaagacag gttaaaagct taggtattaa acgttgaatt taaagcttta atctggtaga  64320 

aacatctgta ctctgattat aattttctaa tttttaagta tattagaaaa tataattgta  64380 

ttgcatgagt agatagaagg gaattatagg aagtcagaat taatattttc aaaggggctg  64440 

ggcacagtgg ctcatgcctg taattccagc actttgggaa accaaggcag gaggattgct  64500 

ggaggtcagg agctcaagac cagcctaagc aacagagcga gaccccgtct ctccaaaaaa  64560 

aaaaaaaaaa aaagtaataa taataataaa cttaaaaatt tgtaaaaaga atatttcaga  64620 

ggtccaatac tttttgctgt gtgccctaag aaaatactta tttgaaagat ggaatacttg  64680 

ctatctaatg gaattgtgat aggaattatt ttataaatca aagatttgtt ttctgtgtcc  64740 

tctgtgtgca caactctgtg ctgggtgcta gtaggtgtgt ttaaagatga ggaaggagcg  64800 

acatggtcct acccttagag taactgtaga aacaagaaga gaataagcaa atgacttaat  64860 

actgacccaa gaaaaacttt tgatcccata tgcattgtaa tagggctttt aaaaaattac  64920 

ataactgctt ttttgtatag tgatagatca tacaatctaa aaataatatt tcaagaatga  64980 

aatcactctt aagacagccc ataatcagct taactgtcaa catcagtttt aggaaatgaa  65040 

aggattgatg tttagtatca aggatagcct atcaagaatg catcaggcac aagaatagaa  65100 

gagtaacaca gaaccaccac aggaagaaag aagcttttac agagagctgc ttttttaaca  65160 

aaaggcgtat gccctatttc atcagtctaa accaccatta ctttaaaggt gttcttgttt  65220 

ccttgtttca tatactacta agagaaatgc tagcaagcct tcatcctgat atcagggata  65280 

ttaattaaaa tgtgaaaaaa aaatttagaa tcaataagta tggttgaaga aaaaaccacg  65340 

gaacaacttc atagttggat taaaaaaaaa tcacaaggaa tataatagtg ggaagaaaat  65400 

cttgtttcct tgattttcat ttcaatcctt tggggctagc tagccaactc tggatttcaa  65460 

attccaactt ttcacacccg tcctcccgcc ccccacaaaa aaactttatc actgttgcct  65520 

agaacaagct aacgtaaaca tgtttatttt gtcttttaat tacttaaatt gtgacctgat  65580 

tagagttttg tacttaaaac ttgacatatc tttgataata aattgaactt ttaaaaaatt  65640 

cctattgcat taacatagtt ttcccagaag acccaaagtt tcgttggaag attagaagag  65700 

ttttattttc atgcagctta ccaacacatg tgccttaact ttctgaagtg gcttttcttc  65760 

acagtctgaa cgtatcagag tctagggaat ggtatgatag ctttattcat cagttcatca  65820 

aacatttact gactgctatg ttaggcattt tgtttggcct gatactctat taaagcctca  65880 

gaaaattgct tgaaatataa aacactagca taccccccag ttttgggtaa acttaaagta  65940 

aatattaaca taataaagta gatatgcaca atggtgattt gatagcttca gggatttact  66000 

ccagtttcat ttttaaagtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgta  66060 

ttcttttttt tttttttttt tttttttttt gagacagggt ctagctctgt tgtccaggct  66120 

ggagtgcagt ggcatgatct caggtcactg caacctccac cacactggct caggccattc  66180 

tcccacctca gcctcccgag tagctgggac tacaggtgca tgccgccata cccagctaat  66240 

ttttggcatt tttttgtaga gagggaattt tgccatgttg ccgagggtgg tgtccaactc  66300 

ctcagcagaa acgatccacc cgcctcagcc tcccaaagtg ctgggattac aggtgtgagc  66360 

caccatactc agccaaaaat gtatatattt ctaataaggt tttatgaatt agcagtgata  66420 

gaaatatttc catctgtaac aaaagactgc tgtaggaaaa tcaccctgac ctactgaaaa  66480 

tgattcttat aaaaaagatt ccccccctca attaattgca gtataatccc tctacttctt  66540 

tccatctttg gcatcagaaa agtaacaaag gaaccttgtt ctttgaaagt tgtcataagt  66600 

ttcccaagca ataaaggtct caaatagaat tacatcctta aagccataat cataagcagc  66660 

tagatttgca tttgttggag cagagtagaa ctgagcagtt gctgcaggct gaccactttt  66720 

cctggggtgc tgggagggca gctagccaac acagacatgc tgaaggacag tgagggtgac  66780 

agaggaagtg agctcaggta caccttgctg gactgctgag cacatatgga agtcacactg  66840 

aacattcaga aattattttt atggaattcc atgctttcat agactctttt ctgttgttgt  66900 

ggtatttgat aaaattccct aaaagcattt tttagagggc cagctattaa aatctttaac  66960 

agggaaaagg ttgcttttca tagttagagt ttatatgtgc atggtttgtg catacagaca  67020 

tttgtctctt tttcttccgt gtcctctcct ctcccgcagt gaagttattc gaagtcattg  67080 

aaactgaaaa aacactctac ctaatcatgg aatatgcaag tggaggtaag aacattttta  67140 

tatatattgg gttttttttc tttctccctt ttaaaaaaat acacaaccat actgcccata  67200 

tgggtcatca ttaaggtctc atttaacgtc cagagccata atacgctagg atgagagtcg  67260 

gaaaagctga ctcttagcac ttctaggggt tgccatgaag tgtttcacta ttagcattgt  67320 

taattggtaa tatctaaata cctggatatt ttttgtggta aaacatgcat cactgaaaat  67380 

tatcgttaaa atcattttta ggcgcacagt tcagtgacat tagcatgttc acgttgccct  67440 

caccaccacc catgtccaga atgttttcat tttctaacac gaaactctat acccattaaa  67500 

cactaactct ccatttctcc ttctcccagt ccttggcaac cattctcctt tctgtctcta  67560 

tgaatttgac tactcttgga acctcataca agtggaattt tacaggattt gtcttttttt  67620 

tttttttttt tgagacggag tctcgctctg tcgcccaggc tggagtgcag tggcgcgatc  67680 

tcggctcact gcaagctccg cctcccgggt tcacgccatt ctcctgcctc agcctcccga  67740 

gtagctggga ctacaggcgc ccgctactac gcccggctaa ttttttgtat ttttagtaga  67800 

gacggggttt caccgtgtta gccaggatgg tctcgatctc ctgacctcgt gatccgcccg  67860 

cctcggcctc ccaaagtgct gggattacag gcgtgagcca ccgcgcccgg ccaggatttg  67920 

tctttttgtg tctggctgat tgatgcagca tagtgtcctc aaggttcatc catgctgtag  67980 

catgtgtcag aatttcattc ctttttaagg ccgaataata ctccattgtg tgtgtgggac  68040 

acacacctca cattttgttt atcttgagta tgtggctatt taaacatatg aatgcttagt  68100 

ctgtttgaaa caaatgtgtg ctttggttta gatgcttttc tttaccagat tttaatgtcg  68160 

ctggtgtctg tcttccccaa ggccagaaat gatggttaca gtacacatca ctagagtttc  68220 

cttaaaataa agattaatga ctagtaacta tttgcctatg gttttgtaaa aatgtagaca  68280 

ttttctgaaa tgcgtgttta tagctgctgt cttttataat gatttgtatt ttatggttga  68340 

gattgggctg ggtttgtagt ttgcgaccac acgtgagttt cattgtctgt gaagggcaga  68400 

agctttcttg ttcatctttt tgtgtcccct gcctctagca cactgcctgg cacacagcag  68460 

atactcaaca gataagaatt agactgcatt taggaattat aaactactgg gtacacattc  68520 

tgttaaactc tatcgtaatt ttatcattag cactttgatc catgttacaa aacctgaaga  68580 

tagaaagttg gattatagtc tcatttgagt gagtttacca ttgaaaataa aaagattgta  68640 

aacctgttgt ggaaaacaat gagttgtagt aagcatacct ttgacaccac ttttttatac  68700 

tcctaattca ttattagttg tgtattttat actttatata tgtctagttt gggaatttca  68760 

ttgggatttt caaaacttca ggggtagtag aaagagggga aggttaattt caggaccaaa  68820 

aagctttatg gagttctaat actttctgtg ggcaaacaac acagagtaat gttcatagcc  68880 

ctcacgttgt acagcctcta cagtgtacaa ggtgctttct cttaccagat ctcctttgac  68940 

cttcacagcg actccatgct gtggccaggc agtgagcgat gggcttttta cccatgagga  69000 

aatggaggct gggaagtctc actgtgggcg ctctgggcct ggaccgccag tgctctgaca  69060 

gcagatagcc tttctagttt gttggtcagt cacggctttc tgttcccatc tgttttagct  69120 

acccaggtca cagagattac tcatataggg gcaagacaaa aacatctaag agtcatccag  69180 

gtttagtaga aagaggatgg gctctggaag agacagacat ggagtgaatc cagccagtgg  69240 

ccctcattgg ccatgtgacc tggcaagtaa catgtgctga gctgagcttc acggtgagca  69300 

taggaacccc ctctgagggc tcagtgcact tggcaacatt gtaagagcct ttaatcattt  69360 

aatcgaaggt ggtggttctg tattaccttg ggtttttttt tttttctttt tggagacagg  69420 

gtctcactct gttgcccagg ctcaagtgca gtggcgccat ctcagctcac tgcaacctct  69480 

gcttcctggg ttcaagcaat tctcctgcct cagcttcctg agtagctggg actgcaggcg  69540 

cacaccacac ctggctaatt tttctaattt ttatagagac aaggttttgc cacattggcc  69600 

aggctggtct tgaactcctg acctcaagtg atccacctgc cttggcctcc caaattgctg  69660 

ggattatagg tgtgagccac agcacctggc ctctttaaca gtgttttgtt gagtttatta  69720 

aaacaatttc cgggacatat gttttattgt tgatgtgttt gccattgtga aaagttttat  69780 

taaattggcc acccattcca ccattgcatc tcccccaccc gccagcctgc tgccttttga  69840 

tttggtaaac tcatagaatt ttagaattga aaataatctt agaaatttta gggcagcggt  69900 

ctaattttta cagatgaaac tgaagctcag aaagtttgtt ctatgccaag gggtccatag  69960 

ctagttagtt tcaggacctg aactagaact aagggctttc tgaactggcc tgtcagtgtc  70020 

cttccatcca gccacctgtt cctgcccagg caggagagcc actctttgct tcttgtttct  70080 

tttatctcta ataaatagcc ttagtatttt tcagttcagc tgcttaacct gaatgttaat  70140 

acatttttaa taaggaaaaa agatctggat tgaattcctg gtttaaaagt tgaactcctg  70200 

aattataatt tagtaattat gagtgtgaca tatggttcca caaatctctt aagaggtttg  70260 

tattgaattc aaatttagaa aaaaaaatct gtcaattata ttgacagact tggattttat  70320 

ctgtgttact ctacaacagc tggtaggctt aatcgtttaa tttttttaag tgaaaactct  70380 

cctatatgat attcactcat gtttagttgt ttttgcttat taaccacttg ttttgacatt  70440 

gtgtgctttt ctgcaaatag gtcattcgca tagaaaatgc tgacacttta ccgagctgac  70500 

atttaacttc ataattcatc atagttaagt gaattgtgtc gtgtaaactt gacagtatgt  70560 

aatgcctttt aaaagatcat tatgcaggct gggcacggtg gctcacgcgt gtaatcccag  70620 

cactttggga ggccaagacg ggcagatcac ttgaggccag gagttcgaga ccagcctggc  70680 

caacgtggtg aaacccccat ctctactaaa aatacaaaaa ttagccgggt gtggtgacgc  70740 

acgcctgtaa tcccagctac tcaggaggct gaggcacgag aattgcttga acgttggagg  70800 

cagaggttgc agtgagccaa gatcgggcca ctgcactaca gcctgggcaa cagcacaact  70860 

ctgtctcaaa aaaaaaaaaa aaaaagcatt atgcaatcaa gtaataacat gaaaatattt  70920 

gtgcccattc attatgtaaa atttattctt tcagagttag ggttaataag agtttcaaag  70980 

tcagataatt gtgtaattca tgatgacttt caagtatcaa aatattttag tttaatattt  71040 

tcactaagct gatggaggta ttccttattt gtatgaagta aagatgtttc ctgaaaacac  71100 

ttatatctaa ttttctaaat tagtattctt ttctattgat ttcagaggtg gtgattcttt  71160 

attctacatt gataagcagt tgacagtgct aataatatat tccttgaagt gtcacctttc  71220 

ttccctaaat aattaatgtt gtgtaaactg ccacctaggc gtgcatcagc tggttctgtt  71280 

gttttcacct ccattgtatc ctgagctcct acttctcacc accactgtgc ttcccactct  71340 

agtccccgtc actttcatga ttggtttgat tattgtactg atctccctct tggtcttcct  71400 

gtcccttccc gtcattggaa gcctcttccc cgctagcagc cagtgatcct tttaagaggt  71460 

cagtcttttt tcatctctgc ttctcatctc acttgtagta gagccagagt cctcaccacg  71520 

gcctacagga ctcttcctag cctcatgaac taccctcttc ccctcattca cacttctcca  71580 

gccctgtggc cttcttgctc tttctcttaa ttactgtgga atcttacccc agataactac  71640 

attgtccaca ccctcaagta gtcagcaaaa cacaagggtg tgcacacaca ggctcacttg  71700 

tctgtctctc ctactttttc tccacagcac ttactgtcct ctgatacact atatgtttat  71760 

tcatttattg ccccctcccc caactagaat gtaaactcta tgaggaaaag gatcttgtgt  71820 

tcactgctgc atctccccag aacctaccta gaacagtgcc ttgcagttag tagacattca  71880 

ggaaatattt gttgaatgaa tgaatatact caggaaatgc tttgttgtca taatcctgca  71940 

gtgaggatgt cctcttctaa cacaaataac ttcatccatt ttaattttct gttttaattg  72000 

cttagttttt attaaagcct attgaaaacg ctctttaaaa taagagttat ataatttaag  72060 

tatagggaat ttaattttaa ggcttttctt cagcttaaag attttgttgg tgaatttaaa  72120 

tgcctgtagt taaagccagc ttagttcaaa ttccacatat ttctggctaa ctttatatct  72180 

atatttaaaa attagagcat tgctaaaagt gaaacatcaa tttatgggaa aattaatact  72240 

cagaagtagg atttctactt acttttattt ctctcaccta taggtgaagt atttgactat  72300 

ttggttgcac atggcaggat gaaggaaaaa gaagcaagat ctaaatttag acaggtatga  72360 

attaatgtgt ctttactatg tcaatttgat aatttatctc acttaaaccc tgaagcaaac  72420 

aagtgtttgc ctccataaat gcttataagg cctgttggat ggcaggggtt ggccattcaa  72480 

ttcaacaaaa attgatgaag aacttttcat acctaaggca ctgtgctgga ggcagccatg  72540 

gttctattcc tagctttgta atgggagcat tagtcttata cttaaccttc cctttttaca  72600 

actgagcctt aaaaatctag agcctttcaa aaacacctgt gattacatta attaaagcca  72660 

tttcagagtt tttagcaagc agaatgtcag aaccccaaaa ttcattatta gctttgtctg  72720 

acataaacca aggccaagtg taactgaaac tgttaattag taactttact tcttgctttg  72780 

tttttactct gctttttaaa gagactcggg ttttaataag caggttttaa gcaaacaggt  72840 

tacttgactc tcctgtcttt attaataata attactgtta tctattgacc atgccacaca  72900 

ctgagataag tactttacca acattaaggt aaatcttaca gctgccttgt gagttaagga  72960 

ctgttatatc catttgctaa aaaataagac aactgagaca tgggaagatt aaataacttg  73020 

cccagaattg cctttctttt tttctttttc ccccttattg tggagaacgg ggtctcgctg  73080 

tattgcccag gcaggtccca gaattgcctt tcaagtagga gacctgccat agactcagag  73140 

tcccaaaccc tctgacccca aaactcagat ttgcaatcat tatattgtgc tattatttag  73200 

actgggaatc agcaaacttc tgtaaagggc cagatagtga acattttagg ctttgtgggc  73260 

cacactgtct ctgtcgcaac tatttaactc tcttgttgta gcttagaagc agtcgtaggc  73320 

tgggtgcgat ggctcatgcc tgtaatccca gcactttggg aggctgaggt gggcggatca  73380 

cctgagggtc aggagttcga gaccagcctg gtcaacatgg tgaaaaccct gtctctacaa  73440 

aaacacaaaa attagccggg catgatggca ggtgcctgta atcccagcta ctggggaggc  73500 

tgaggcagga gaatcgcttg aacctgggag gcggaaattg tagtgagcca agaccgtacc  73560 

attgcacttc agcctgggtg acagagactc catctcaaaa aaaaaaaaaa aaaaaaagaa  73620 

gcagcagctg tagacaatac caaatgaatg aacgtgactg tgttccaaca aaactttatt  73680 

tacaaaaaca gggatgggcc ggatgtagcc agaggccata atttgccaac ccctgattta  73740 

gacgaaggaa aggagcagtg cttcactgct tttaaattaa ttctgtattc tcacaaggcc  73800 

tacattgaaa tggaattata gcctcatttt ttcttagaac ctttatattt tgttttattc  73860 

atatacaggg ttgtcaagct ggacagacta ttaaagttca agtctccttt gatttgctta  73920 

gtctgatgtt tacatttgta agtgatagga cttattaagt ttcttataaa cgttgcttat  73980 

attttgctgt tgcttaaata ctaatggtac tttgaattca aatctagtaa aaccaaagta  74040 

aaaatcagct ttggctatca tttaacttct ctgatcctgt ttttaaagct ataaaaaaaa  74100 

aagaaattat tcttgatgaa ttccatagtt ctttgcaatt ctaatataat ttgattgtat  74160 

ggtctattaa aggaaattca gatttttatt agaaaaaaag tgtgtggctc tttccataac  74220 

tgtactctta atttttataa attggccacc taaaagggaa catttttttg cttcatacaa  74280 

tttacattcc ttcctactca gatgaatctg acttgcaaac atgtgtgaag atggcttatt  74340 

gactatgagg aaggggctgg tgtcacccag caagagctta ctaacctaaa tcttgaggaa  74400 

attactctaa tttttattgt aaattccctg cagaaattct gaagccttta tttgaggagc  74460 

ctgttagttg gactaggaaa gatggtttgt atgtatgtgt tttttcaatt agcaaattga  74520 

tttagagtgc tttagaattg accctttctt ccatggtatt tgcctaaaac agctccatta  74580 

gacttggaag gatacgcatc atattggtgt ttccactttt ctgtttcaaa tgctgtggtt  74640 

tctttgtttt ttcgtttttg agatggagtc tccctctgtc accaaggctg gagtgcagtg  74700 

gcccgatctc agctcactgc aacctccgcc tcccaggttc aagcaattct cctgcctcag  74760 

cctcccaagt agctgggatt acaagtgtgc accaccacgc ccagctaatt ttttattttt  74820 

ttttttgtaa ttttagtaga gacaaggttt caccagtgtt ggccaggctg gtctcagact  74880 

cctgatctca agtgatctgc cctcctcagc ctcccaaaat gctgggatta cagatgtgag  74940 

ccatcgtaat gtggcctcaa tttctgtgct ttctaggagc ttataagtca taattacttt  75000 

gactaagtaa aacaagtttt tctatttatg acaaaaagga aggtatgcca cacacaaagt  75060 

acactgtgtg tgatcccttt tccatattca tcaccagatg ggttttcccc ttctgcttcc  75120 

ttcaccatgc ccatcctagt tactgcttat gacattttaa ttttttggtt gagctcattc  75180 

ttttccaaga aaaagaatag atttccagct ccatcttttt tttttttttt tttttttttt  75240 

ttttttgaga caaatctcgc tttgtcgccc aggctggagt gcagtggcgc gatctcggct  75300 

cactgcaagc tccgccccct gggttcacgc cattcttctg cctcagcctc ccaagtagct  75360 

gggaatacag atgcctgcca ctacgcccgg ctaatttttt gtatatttag tagagacagg  75420 

atttcactgt gttagtcagg atggtctcga tctcctgacc tcgtgatcca cccgcctcgg  75480 

cctcccaaag tgctgggatt acaggcgtga gccacgcgcc cggcacagct ccatcttttt  75540 

tacttacctc tttattggtg ggctggtaat attgatgatt tgacgctctt ttatgtatga  75600 

ttgaaagtga attaggttaa atcatagttt aacctaaata acatctgtta gaaatcacca  75660 

tttctacctg gtaatagaat gcaaaaaaag cagtaagttc aagttgagtc ttttcagctt  75720 

attgtggcat caggttagct ttgagctgtt ttggagctaa agagagagag aaatcctttg  75780 

atctctttga gaaagggcag gaaatcaaat ctgcttcaaa agcagaattt gaaaataacc  75840 

tgtaagagaa atctcaatat gaggaaaaac taatataaat tctgaatgag aaaaggaaaa  75900 

agattagata aaatttacct gtgtcctagg tgacaaagct atgactttgt tttgggaaaa  75960 

caaagctatt ttacttttca agttttcatg ctgactgaat agaacaatag tgataaatcc  76020 

aaagtaacag atgctctaaa acccgttttt tggcattgga atttttgtac cttttgttaa  76080 

ttataagtgg gtctgatatt ctgaatgtta attttaaata atgaagctgc ttagtaaagt  76140 

gctgattttt gttatcatct catcctaacc ccagttcacc ttgtccttgc tgcttattct  76200 

gaaccaaaat attatacagc cctctgagat tttatgtcca cgggtgggtc catggggctt  76260 

agagctaaga gttgatgatg atttggagga accaacagta attttattat aacctcagtt  76320 

ttgtgtatat gtaatcatat gtgtctaaat atacatgcag aataccaaag aaaagactag  76380 

atgcaagtac agcaaaatag caagacatgt tacctctgct tagtggtaat gcaggaatat  76440 

atttctatag acttttctgt atttcctgaa atttctacaa tgaccatata aagctttaat  76500 

attagaagac tttttttaag tgaccgtaag tgtgaaattt cagtaaaaca attgtttaat  76560 

cataggcatg actgcaagtt gactaaataa aagcatacta tttactgaaa gtgggaggaa  76620 

tccttaatag tgcacgtagt agttttcata gttcacgtac gtcgcaacat tcattcctcc  76680 

attttaataa aggaagagga aactgaccct cagagaagtt aactaacttt tgctttccat  76740 

gatccacatc agttagaagg aagactgttg cagggagcag gctgagaagg gcacttacag  76800 

aagagagcca acctggatta acacctgggt atgggcaact ctctaaccgc tggtttggtt  76860 

tggagttgac tctatgggta tggaaaggtt gcaccaggcc gggcgcagtg gctcacacct  76920 

gtaatcctag cactttggga ggctgagact ggcggatcac ctgaggtcag gagttcgaga  76980 

ccagcctggc caacgtggtg aaaccccatc tctactaaaa atacgaaatt ggccgggcat  77040 

ggtggtgcac acttgtaatc ccagctactc gggagactga ggcaggagaa ctgcttgaac  77100 

ctgggacggg gaggttgcag tgagccaaga tcatgccatt gcactctagc ctgggtgaca  77160 

gaacgagact ctgttaaaaa aaaaaaaaaa aaaaagttgc accagagcca tcggagccta  77220 

ggggcagcca gggtcctcca gatctaggca atttgttggg tcctggcact acactgtaag  77280 

tggaatgtca acggataggg tccaaaaaga gacttcagtt aaaacagtag aaaacggaag  77340 

aacgtcctca cctatttgtt tttgccctca cccatgaatt tctccagact ggaaagttca  77400 

aggcatagga aaattgtttt tagaaatcca cacggacatt cgagcgtata ctgagtattc  77460 

attatgtgtg aacattaaca aagttatttt catcttaatt acgaatctgc accagtgatg  77520 

actgactctg cgtctctcct attcagattg tgtctgcagt tcaatactgc catcagaaac  77580 

ggatcgtaca tcgagacctc aaggtgagta gaagtgcctc actcagtgta tgctctgtct  77640 

gtttgtgtgc agttctctca gtggtcatta cacaaatgag gtatagatta gccttattag  77700 

cattttttaa aatcccacaa taattgaatc ctcttaatca agttatggga aagagcatta  77760 

aaaataaaga aaaataaagg ttattgaaag tattttacat ttcagttacg gtgactggtg  77820 

gttgatctct ggagaacagt catcacacag ccaaacaaat gtgggcctcc agaaatgtat  77880 

ggtcacgccc acagcatcct cagtgccacc cggcattcat ttctgctgct ttcatcagta  77940 

ttctctcccg ttaacagcag tgcctgtttg agacctcttt caaggtcctc agcctctgcc  78000 

ctcactctgg cataggatga ggtttcgtat cgcacagaga aaatagaaac accatgcaga  78060 

aactctcatt ttctaccagg ccctcaaacc tagcagcacc tacccccatc catcacttct  78120 

ttcctcctgt tacaggaaag tggggtgctt ctgctctgag ctctgggtcc tgattccctc  78180 

tgggggctgt gctctgtctg atgcctcttt tctctccgtt tgtttattca ctctccttct  78240 

ctactggctt ttcaccagca gcatttacac atgctcaagt ctatatacct tttttttttt  78300 

ttaactaaaa agccatgcct gttcctcttt cagatacacg ctttttctct cttccctttc  78360 

atagccatat ttctctaaac atttcctaga ttctgtgtct taacttggca ctcactttca  78420 

ctctcccctt acgtaattgc cattgacttg cttgttctct gcacccgccc ctagagcatt  78480 

cacattcact ctctcaactg cagtggccaa ctgtatgctg atggccccaa atccattcct  78540 

acggccagag cactcttctg ggatccagga cccagctgag caaagggtgt cttcatataa  78600 

gcatcccttg ggtgcagcag gttcaaatcc tataaacatg aatgttcact tctcattcag  78660 

gtgtctgatg tccctcaagt accttactct cctgtgctac ccactcagtc accaggtcct  78720 

tttgctgctg tgttccaagt atctcttaag ctcactcttt tatgtccctg ttacactatc  78780 

caaggccaga ccaccattat ctcataggtg attccgacac tactttctta tatgttcttc  78840 

tctgtttcta gtgcctcttc ctcccatgta tgttttctac actgcaccca aaatggtctt  78900 

ttaaggaaac acaaataaga tggtcatttc tctgcttgaa caactcttca ttggcttccc  78960 

attgctctta cgatgaaaac ccaaacttct caagtacaat cctttgtgat taagccctga  79020 

ccatctcccc agccccctct acacatctct atctcacata ctgtctttca atttcttgtg  79080 

tgaaacatac tgtgtctcac atgggttctc agactcttta ttctgcctga aatacccctc  79140 

atcaacacat ccattatgat cagatgcacc ttctggtgct ttgatttcac ttcatctggg  79200 

aagccattca cacctttcag tgccaaccca caactccctg tgcctcttca gttatggcat  79260 

tttgtctcag gacagctgct tatcattctc cttcttccct tctaaactgt gagctactga  79320 

gggtagggct ttatctgtct tgttcatcat tatccatcca gacactaata tagcatctgc  79380 

tgtggagtag ccacatagga aatgtttctt aaagtgactg tgatttgtct cttttttttt  79440 

tttttttttt ttttttttga gacggagtct cactttgttg ccctggctag agtgcagtgg  79500 

tgcgatctct gctcactgca acctccacct cgcaggttca agcgattctc ctgcctcagc  79560 

ctctcaagta gctgggatta caggcgccca ccaccatgcc cagctaattt tttgtatttt  79620 

tagtagagat ggggcttcac catgttggcc agactggtct cgaactcctg acctcaggtg  79680 

atccacccgc ctcagcctcc caaagtgctg tgattacagg cgtgagccac cgcacccagc  79740 

catgatttga ctcttgaatg aggtttagga ttctcccctc ctcattaaca gccgttttat  79800 

agctatttag ccgtttttat gaaatgcccc tttttaaaaa aagttattta tgttttgaga  79860 

cagggtttta ctctgtcacc caggctggag tgcagtggca cagtcatagc tcactgcagc  79920 

ctcaaactcc caggcttaag aggtcctcct acctcagcct tccaagtagc tgggattgca  79980 

gatgtgtgcc accataccca gctaattttt aaaaatcttt tgtagagaaa gggtctcact  80040 

atgttgccca agctggtctt gaactcctgg gctcaagtga gccactgtac ctggccctgc  80100 

cccatattat tcttgttttt tggttttgag atggagtatt gctctgtcgc ccaggctgga  80160 

gtgcagtggc acgatcttgg ctcactgcaa cctctgcctc ccgagttcaa gcaattctcc  80220 

tgcctcagcc tcctgagtag ctgggattac aggtgtgtac caccacaccc agctgatttt  80280 

tgtattttta gtaaagacag ggtatcacca tgttggccag gctggtcttg aactcctggc  80340 

ctcagatgat tcgtccacct cggcctccca aagtgctggg atcataggtg tgagccaccg  80400 

tgcccagccc ccatattatt attatcaatt gaaaaactca aggcttttct tgatcttggg  80460 

acattgatgt ttaaattagt gctagaatta atctgtactt catgtttgtt attgttaata  80520 

ttataaaata aggagttctg acttgtctcc tgtttttttc tctagaaaga atgttttcac  80580 

attaattagg aggtaacttc atatcattac agaaagcttt tctaaaatgc ctaatcctgt  80640 

cataattcta attctatttt ggctaaattt catttttgtc ttgatgtttt ccctctaggc  80700 

tgaaaatcta ttgttagatg ccgatatgaa cattaaaata gcagatttcg gttttagcaa  80760 

tgaatttact gttggcggta aactcgacac gttttgtggc agtcctccat acgcagcacc  80820 

tgagctcttc cagggcaaga aatatgacgg gccagaagtg gatgtgtgga gtctgggggt  80880 

cattttatac acactagtca gtggctcact tccctttgat gggcaaaacc taaaggtata  80940 

agaagctgca cccatgtact tcactaaact aaaagaagtt tcctaatatt acatggctta  81000 

atatttttaa cattatatca gtgcgggggg tttcaggggg ttttttgttg tgttttgtta  81060 

actaaaccta aaggttgact tactcgtttt ctttcctctg tacctctcca aaggaactga  81120 

gagagagagt attaagaggg aaatacagaa ttcccttcta catgtctaca gactgtgaaa  81180 

accttctcaa acgtttcctg gtgctaaatc caattaaacg cggcactcta gaggtaatca  81240 

tgtaggtgga aacaagcagt aactttggag agtctttaga gtgaccttag atctttgctt  81300 

gatttgtatg ccatactgga tatatcctgc ggctttttaa gcaagaattg aaacattaaa  81360 

aaatattttt tgagtttatg ctttgaacga tagtcaatga aatgttgaaa ataaattttt  81420 

gtaaatatta cggttatcag aatatttcat tttactctgc taatgaacag tttacctttt  81480 

ttagcaaatc atgaaggaca ggtggatcaa tgcagggcat gaagaagatg aactcaaacc  81540 

atttgttgaa ccagagctag acatctcaga ccaaaaaaga ataggtaatc actccatgcc  81600 

tgcatgttca tgtgtttttg tctaagtaac atatttctgt tttgactcat gtctgtgcct  81660 

aaaatgtgaa taatggaaag ttaagcacaa gtcatatgaa cagtttatct gttctgtcat  81720 

atttaggaac gtaactacct gcagtttcct ataatggcac ccagtaactc tgaaacaagt  81780 

gcccatttat gttacaaaat atatgtaata tgtcatcttt taggtcaaat gaaaattatt  81840 

ttaccctaca aaagaatgat ttctggccgg gcgtggtggc tcacgcctgt aatcccagca  81900 

ctttgggagg ccaaggcggg cagatcacct gaggtcggga ggtcgaggcc agcctgacca  81960 

acatggagaa accccatctc tactaaaact acaaaattag ccaggcacgg tggctcatgc  82020 

ctgtaatccc agctactcgg gaggctgagg caggagaatt gcttgaatct gggaggtgga  82080 

ggttgcggtg agccaagatc gcgccattgc actccagcct gggcaacaag agtgaaactc  82140 

cgtctcaaaa aaaaaaaaaa aaaaaaggat gatttcttac ccaaacaaaa cacataaact  82200 

gtattatgcc cttcttttag atattatggt gggaatggga tattcacaag aagaaattca  82260 

agaatctctt agtaagatga aatacgatga aatcacagct acatatttgt tattggggag  82320 

aaaatcttca gaggtaagag taatcagaaa gagctgaaat accctgtatg taattattag  82380 

tttatataaa ctgttttctt agtttttatc ttttgaatat ttgtaacatt tgatacatca  82440 

ttttttagat ttacttgcaa atagcaaatc taaatcctat gactattata agctatttta  82500 

acttaaccct taatgatgga tattggccag gcgtggtggc tcatgcctgt aatcccagca  82560 

ctttgggagg ccaaggcgga cagatcactt gagaccagga gttcgagacc agactggcca  82620 

acatagggaa actctgtctc tgctaaaaca aacaaacaaa caaaaaatta gctgggcgtg  82680 

ttggcgcttg cctgtaatcc ctgctccttg ggaggctgag gcaagagaac tgcttgaccc  82740 

tgagaggcag aggttgcggt gagccaggat cacgccactg cactccagcc tgggtgacag  82800 

agcgagactc tgtctcaaaa aaaaaaaaaa aaaaaaaaag atggatgttg tcataaacct  82860 

ggtctttcat aaattaacct gtagtcatta atagcttaga aatgacgtaa agcatcagat  82920 

gaagtaaata caacatttaa agttatttga gaaagcctgg aaagaaaatc ataaatacct  82980 

tacctttagt gtctttccag ccgtcagaaa actacttttg cttgagttta gggttgtcat  83040 

ttttgtacgt tgtgattcct cctctctctg aatgaacggt ttatgagagg tctgtgttaa  83100 

tgaaaagttt aacttcctaa taagccattt gggttcgtgt tgtggtttgc tctgtttttc  83160 

tcattttctc ttagctggat gctagtgatt ccagttctag cagcaatctt tcacttgcta  83220 

aggttaggcc gagcagtgat ctcaacaaca gtactggcca gtctcctcac cacaaagtgc  83280 

agagaagtgt tttttcaagc caaaagcaaa gacgctacag tgaccatggt aagttttgga  83340 

gtatcccagt gccttctctt agagtccagg caagaggtct cctagcactg ggaagcattc  83400 

tcttgctcag agcctggctt gatgtccttt cttggcattg ctttctttct ttcttctttt  83460 

tttttttttt tttttttttt ttttgagaca gagtctcact ctgttgccca ggctggagtg  83520 

gagtggcaca attttggctc actgcaacct ccacctccca ggttcaagcg attctcctgc  83580 

ctcagcctcc tgaatagctg ggactacagg tgtgtaccac catgcctggc taagttttgt  83640 

atttttagta gagacggggt ttcaccacat ttggccaggc tggtcttcag ctcctggcct  83700 

taagtgatcc acctgccttg gcctcccaga gcgctggaat tacaggcatg agccaccgtg  83760 

cctggccagc attttttctt agtgttcctg caggtgctgc catgattaca tattacttca  83820 

aggctcttat cttctttata catgcagtag atttttgctg gataaagctt agttgagtgg  83880 

aaaccttacc atttgccctt ctagaacctc tgctttaatc tgtagttttc cttttttttt  83940 

ttttttttaa atggagatgg gggtctcgct atgttgccca agctggtctc aaactcccaa  84000 

gttcaaacta ttctctcacc acagcgttct aaagtgctag gattacagac gtgagccacc  84060 

atgcccagcg ctagaactgg gcgctgtacc gaactgaata gaactgctag tctgtagttc  84120 

tattcactct cttcacctct gcattggatt tactttgtag agtagcactg tccagtagaa  84180 

ctttctgaga tgattacagt tttgtgtatc tgtgctgtcc agtcaagaag ctactggcca  84240 

cttgtggcta tcaagtactt gaactgagga aatgattttt acctttttta tttctattta  84300 

ttttttatta tttttattta tttatttatt tatttatttt tcagatggaa tctggctctg  84360 

tcgcccaggc tggaatgcag tggcatgatc ttggctcact gcaacctcca cctcccaggt  84420 

cccagcagtt ctcctgcctc agcctcctga gtagctggga ttacaggcat gcacaaccac  84480 

acccggctaa tttttgtatt tttaatagag acagggtttc accatattgg ctaggctggt  84540 

cttgaacttg ggagctcaag caatccactc accttggcct ccaaaagtga tgggattaca  84600 

ggtgtgagcc accgcgcctg gccttattta tttgtttatt ttttgagatg gaattttgct  84660 

cttgttaccc aggctggagt gcaatggcat gatctccgct cactgcaacc tcagcctccg  84720 

aagtagctgg gactataggc acacaccacc acacctggcc aatattgtat ttttagtaga  84780 

gacgggattt caccatgttg gccaggctgg tctagaactc ctgacctcag gtgatccacc  84840 

caccttggcc tcccaaagtg ctggattaca cgtgtgagtc tgtaattggc ctggctgatt  84900 

tttacccttt taaaattttc ctggccggac atggtggctc atgcctgtaa ttccagcacc  84960 

ttgggaggcc gaggcgtgtg gatcactagg tcaggagttc gagactagcc tgaccaacgt  85020 

ggtgaaaccc catctctact aaaaataaaa aaattacctg ggcatggtgg tgtgtgcctg  85080 

taattccagc tactcaggag gctgaggtag gagaatcgct tgaacctggg aggcagaggt  85140 

tgcagtgagc caagatcgtg tgactgcact ccagcctagt gacagagtga gagtccatct  85200 

caaaaaaaaa aaaaaaaatt tgtacttaag tgtaatatat agccagttgt ggccagtaac  85260 

tctcataata gacaggacag ccctggagaa tatatggaac ctcagttttg ccttaattgg  85320 

tttaaatgtt gtactgtgtc attctcatcc atactcttgc tgttagtgtg gttaagccac  85380 

tctccctttt aaacttcacc tagaagccag tcctttatga gacataagac tcccagtggg  85440 

taggcttacc aggctctaca gttgctctgc cttcaaggca gcctgtgtgt cagagtcctg  85500 

aggctagcgt gtgtgtttac ttgcccataa ctataaatgt taacattgca gatatttcct  85560 

ttaattctac tattccagga ttcaggaact aaatctattt tttttttttt ttttgagatg  85620 

gagtttcact cttgtcaccc aggctggagt gcaatagcgc gatctcggct cactgcaacc  85680 

tccgcctcct gggttctagc aattctcctg cctcagcctc ccgagtagct gggactacag  85740 

gcatgcatca ccatgcccag ctaatttttt tatttttagt agagacgggg tttcaccaca  85800 

tttggccagg ctggtcccga actcctgaac tcaggtgatc catccacctc agcctcccaa  85860 

agtgctcgga ttacaggcat gagtcactgc gctcggcctc attttatttc tcttctctgg  85920 

acattttcca tcttaatact ttcatcttga gatttgacac ttaggactgc acagggcatt  85980 

ttaggtgtgg acagctttga ttttgtacta aaaatgatta cacttggctt gatttccatt  86040 

tctcttcctt ctgttgcttg cctttctaca tggtttagac tgaagcaaca gtgtactaat  86100 

atcactagta aaccatctac agtgcctgct attctagggt gtaactgaga gctcagaact  86160 

cattctcaca tcaggatttg tgctcctagc atttgtaggt gacgtgttga tctaggtctg  86220 

ccttttttgt gttcatgtta gtcactaaca aggggggttt ctagtgctta tggaccacat  86280 

ggcaattaaa tgcccatata ttgccctgaa accatctggt ttaacttgtc cctcaatcct  86340 

agaagaaacc tgacaatggg attttcacat ttctctaagg aatatgttag taagttattc  86400 

cttaagcaca tagattccat ccagattatt agtgcctttt tccccccagc tcaattttag  86460 

agataaaaag agctttagac atggtattgt acactcacca aacctctgtt ttatccctaa  86520 

atagaccaag agagattacc aagtctccca aggttacata gtaaatgaga aacacctggg  86580 

gcagagctca ggcctgctgg tccaagccct gtgttttttc tccactgaag cacctcattg  86640 

gagtagcttt ttcataatcc tcatctttct tggaatttct gaaggcaggc aagcctgtat  86700 

agccgggcta actttcacct catcctcctg cctcgtctca cctctccctt cccttttcct  86760 

tgcctgtgga tgctgacctc tgcatgggtg cctgcttctc taaagctacg atgtaatctg  86820 

tagctgtcct tcctcgtttg agacccacat gtgaacaccc catatgtgtg cactttttct  86880 

gcgaatggtg atcatctgat tttcaagggg ttagcttgtt ttttaaaaaa tgaaaaaaaa  86940 

aatcactgtt tactaatcaa tgagtggtat tggggcaatt tggtagttct cagaaaaaaa  87000 

attaatttgg atcaatttct cacatcttat acaaggatga attctaattg gagttaagat  87060 

acaaatatag ggctgggcgc agtggctcat gcctgtaatc ccagcacttt gggagtccga  87120 

ggcaggtgga tcacgaggtc aggagatcga gaccatcctg gctaacatgg tgaaaccctg  87180 

tctctactaa aaaatagaaa aaattagcca ggcgtggtgg tgggcaccta tagtcccagc  87240 

tactcaggag gctgaggcag gagaatggat gaacccggga ggcggagctt gcagtgagcc  87300 

gagatcgagc cactgcactc cagcctgggc gacagagcga gactccgtct caaaaaaaaa  87360 

aaaaaaaaag atgtaaataa aactccagaa atattgaaag aaaccttggg attatttgct  87420 

ttgtaacttg gactggtgaa ggtgtttctg tcaccccaaa caccaaaccc atgaaataaa  87480 

agacttacaa atttgattac ataaaaatga aatttctggc cggtcgcata atcccagcac  87540 

tttgggaggc cgaggtgggc ggatcacgag gtcaggagat cgagaacatc ctggctaaca  87600 

cggtgaaacc ctgtgtctac taaaaataca aaaacaaaat cagctgagct tggtgtcaag  87660 

tgcctgtagt cctagctgct caggaggctg aggcaggaga atggcgtgaa cctgggaggt  87720 

ggagcttgca gtgagccaag atcatgccac tgcactccag cctgggccaa cagagcgagg  87780 

ctccatctca aaaaaaaaaa aaaaaaaaat gaaatttctg tgtgacacat ccataccatg  87840 

gactactact cacaataaaa aggaacaggc tgggcgcggt ggctcacgcc tgtaatccca  87900 

acactttgag aggccgaggc aggcagatca cgaggtcaag agatcgagac catctggcca  87960 

acatggtgaa accccgtctc tactaaaatt acaaaaaatt agccgggcat ggtggcaggc  88020 

gcctgtagtc ccagctactt gtgaggctga ggcaggagaa tcgcttgaac ctgggaggtg  88080 

gaggttgcag tgagccaaga ttgagccact gcactccaca gcctggccac agagcgagac  88140 

tccgtctcga aaaaaaaaaa aaggaacaaa ctatgatgtg cacaactcag atggatctca  88200 

agggaattat actgcatgaa agtacacaaa aggttacatt ccatggatgc ccattcatat  88260 

aacattcttg aaatgacaga attctagaga tggcgagcag gttagcggtt gcaggggttt  88320 

agcaaaaggg agagtaagag ggaagtggct gtggctatga aagggtagtc tacagggtct  88380 

ttgagatgga aatgttctga atcttgactg atggtgacca catgaatctg aacatgtaat  88440 

aaaagagtat agaatgagat acacaaacat acaaattagt gcaagtaaaa ctggggaaat  88500 

ctgaacgagg tcagtggatt agatcaaggt ctgtttctct tcagaatctc aaatcttaaa  88560 

aggttttgta ttttctaaac acaaataaaa gctggaaagc caatcagtag taatctgaaa  88620 

gttcacaatg tcagtagacg tctcatggta ttgggaagaa agataagcat tgaggctaat  88680 

atcaccctat gcttgattaa gtttttgttt tatatgttaa aatcactaaa ccgaaagctt  88740 

agttgttgtt ctcccacaaa taaaattaag ccctcattta cttttaattc agttccaaat  88800 

aggtttgcca tttagatttt tgtccaagaa ctaactcctc cccactcccg gtttttgttt  88860 

gtttgttttt taaatttatt tattgagaca ggttctcact ctgtcaccca agccacatgt  88920 

agcctcaaac tcttgagctg aagccatcct cccacctcag tctcccaaag tgttggaatt  88980 

acaagcatga actaccacac acctcccacc tttaatatat ctaaaatata aattctcttc  89040 

tgccttagaa aaaacaggct gggcgcagta gctcatgcct gtaatcacag cactttggga  89100 

ggccaaggtg ggtggatcac gaggtcagga gatcgagacc atcctggcta acactgtgaa  89160 

accccgtctc tactaaaaaa aaaaaaatat atacaaaaaa aaaaaattag ttggcatgcg  89220 

cctgtagttt cagctactcc ggaggctgag gcgggagaat cccttgaacc cagtaggcag  89280 

tggttacagt gagccgcgat tgcgccactg cactccagcc tgggcgagag agctagactc  89340 

cgtctcgaaa aagaaaaaac aagcatttga ctctgtcttt taagattacc actggattat  89400 

catatctgag gcatatacta gttatcatgt tcatttccaa gattctttgc cctctgaatc  89460 

tcctgtgctg ctattggagt ctctatatgg tttactacag gacattagtc tgtcatccac  89520 

atgtccctag gcacatgtcc ctggacacac tcctcctgga gtggcaggaa tgactagtga  89580 

cctccaccga cttcctccct gtcgcttgca tgattcctct gcttctacac cttcccctgt  89640 

ctactcaaac tccggtttat ctagaagatt atgagtgctt ttaaaaagat ccaagataaa  89700 

acttcaaaag aagtggccca taaaatctat acttttctct tccaaaaggt gatggcatct  89760 

ctcctacaaa agaggatgta attcactcag atgtacaaga tgaactggtt cattctgctt  89820 

gttacgtatg catctaatta gtttgaatct atgcagtacc accaccttaa gatgtttcca  89880 

aaggacaact ctaaactctt actattaaaa aaaaaatgtt ttaagtagaa aggagtatta  89940 

agtgaaattt caatattgaa ttcattgcat aaggcaaaca ttagatataa gtgggaaaca  90000 

tcttagagga ttttactgtt ttacattttt taggtgaata gcaaccttag atcatcttac  90060 

aaaatatggt tactgtcaca aaataaaact tgaaactata ttcagtcatt taaaaaatga  90120 

actctttatt ttagctggac cagctattcc ttctgttgtg gcgtatccga aaaggagtca  90180 

gaccagcact gcagatagtg acctcaaaga agatggaatt tcctcccgga aatcaagtgg  90240 

cagtgctgtt ggaggaaagg gaattgctcc agccagtccc atgcttggga atgcaagtaa  90300 

tcctaataag gcggatattc ctgaacgcaa gaaaagctcc actgtcccta gtgtaagtgt  90360 

tgttgaacta tagagtggtc ttagggtggt agggttggaa ccagctagac accaggtgtt  90420 

cattttactc ctgtggtctc tcgtactgga atgccctctc tactaggcag ccatgcccaa  90480 

tcttaactta cagaaatcct acctgctgca ttgtaggtat ttattgttga cactctctta  90540 

gttcattctt gctgctgtaa caaaatacct gagactggct aatttataaa gaaaagacat  90600 

ttatttctta acaattctgg aggctgagaa gtccaagatg aaggcaccaa caagttccgt  90660 

gtctggcaag ggccctgttc tctgcttcca acatgatgcc ttggtgctgg catcctccag  90720 

aggagacaaa tgctgtgttg tcatgtggct gaagggacag aaggggtgaa ctcaccccct  90780 

caagcccttc tataaaacac taatctggcc gggtgcggtg gctcacgcct gtaatctcag  90840 

cactttggga ggccgaggtg ggtagatcac gaggtcagga gttcaagacc agcctggcca  90900 

agatggtgaa acgccatctc tactaaaaat acaaaaatta gctgggcgtg gtggcaggca  90960 

cctgtaatcc cagctgctca ggaggctgag gtagagaatt gcttgaactc aggaggcaga  91020 

ggttacagtg agccgagatc gcatcactgc actctagcct ggcgacagag cgagactcct  91080 

tctcaaaaaa aaaaaaaaag atactaatcc cttcatgaag gcggagccct cgtggcctaa  91140 

acacctaaaa gactcatctc caaatactgt tttctcctat gggagataaa gcttaaacat  91200 

gagttttgga ggggacacat tcagagcata gcacacccac catagacact agatggtgat  91260 

aggtccttta tttcaaggcc tggttccagt tatttcggac acctgctgag ccttaggttg  91320 

tcaggtgctg agacatggaa agacctcaca gtctaacagg aagtgaatga aaacagtgac  91380 

agtgcagatg gaagcctacg tgcacacacg gggaggtctg actgccagtg ccccaaagat  91440 

gtggtgttca cactgagtct tcaaagagct ctaatgatga agagtgttgg ctgagttctt  91500 

accatgtgcc aaggaccatg ctcagtgctt tttcatggat tagctacatt ttaaggtgaa  91560 

aaaaaagttg ggtaattgcc taaaattaca ctgccaacct gaatccagct cttaatccct  91620 

atctgtaaca aaatctcccc agtaagtaga taatatttac taaattaaat tgaatccatt  91680 

cagcttcaga aacttttttc tgtgtattga agtatgttct atctaaccta acatattaaa  91740 

gaatttgcag agaagtaaac aatcttaaga ttattctgta agcacgtttt tccctacaaa  91800 

attaacaatg atgcagccct gcctccaact ccagaaaaac cctggactga ggaggctgtg  91860 

gagaaaccct gttgctctct gaaagccctt cattgttcca ttctggggac tgggtgcatg  91920 

aaggacccca aggggctttg catgtttcat cctctgacct tatgcttagt cgaagtaaac  91980 

cctgtgtgaa aagtttattt tggcctccaa atgccataca gtaggattat tgtttccata  92040 

ctcctgcagt taaaattccg tctccaacgt ttgttgacag ttaccagaga agatgagggc  92100 

attattccct gccttcatga cttctcttcc cctttgctct tgtctacaca cgctgccctt  92160 

ctgaaagtga atcatgagta ttttcagtcc acccatacta aattacttac aaaggaaaaa  92220 

aggtagttag caacattatt attttctccc atgagtcttt gggatttctc tgtagatggt  92280 

ctgctcaagc tgtagtaaaa gtgactgctc tatctttgtt taaaaattat ctgataaaat  92340 

tccatagcta tggccaggca cggtggctca cacccgtaat ccctgcactg tgggaggcca  92400 

aagtgggcgg atcacttgag gtcaggagtt caagaacagc ctggccaaca tggtgaaatc  92460 

ccatctctac taaaaataca aaaattagcc gggtatagtg gcgtgctcct gtaatcctag  92520 

ctattcggga ggctgaggca ggagaattgc tttaaccgag aagatggagg ttgcagtgag  92580 

ctgagattgt gtcattgcac tccagcctgg gtaacagagc gagactccat ctcaaaaaat  92640 

aaaaaaaaaa gtccatagct gtgacttgtt ccttgctttt tagttttttg ttttggaagt  92700 

taaattcatg tgaatccaca tgacaatgat taaccatttt aaagtgggca atgcggtggc  92760 

atttggtaca ctcacagtat tgtgcagcca acacctgtct ttagtttcag aactttttca  92820 

gctccccaga aggagcatct gtttaggctg ggcacagtgg ctaaccccta taatctcagc  92880 

gctttgggag gctgaggtgg gaggatcact tgagcccaag agtctgagat cagcctgggc  92940 

accagagtga gacctcatct ctacaaaaaa aattaaaaag aaaatagctg agcgtgatga  93000 

tgcacacctg tagtaccagc tacttgagag cttgagaggc tcaggtggga agatcatttc  93060 

agcccaagag gttgaggctg cagtgagtca tggtcacatc accatattcc agcctgggca  93120 

acagagcaag accctgtcct taaaaaaaaa aaaagtggcc gggcgcagtg gctcacgcct  93180 

gtaatcccag cactttggga ggctgaagtg ggcagatcac aaggtcaggc gttcaagacc  93240 

agcctggcca tcatggtgaa accccatctc tactaaaaat acaaaaatta gccaggcatg  93300 

gtggcgggca cctgtaatcc cagctactcg ggaggctaag gcaggagaat cgattgaacc  93360 

caggacgcag aagttgcagt gagccgagat ggtgccactg cactccagcc tgggcgaaaa  93420 

agcgaggctc catctcaaaa aaaaaaaaaa aaagaacacc tgtatccctt aagtaatcac  93480 

tttccattcc tcctctcccc tctgcccccc tcccttcccc ctcattccct ggcaaccacc  93540 

agtctgtgtt ctgtctctgg atttgcctgt tctgaatatt ttatataaat ggaaccattt  93600 

cacatgtatc cttttgtgtc tacttctttc tttgactcag cataatgttt tcatggttca  93660 

tccaatttgt agcatgtatt ttcttttccc tttttttttt tttgagatgg catttcgctc  93720 

ctgttgccca gagtgcaatg gcacgatctt ggctcactgc aaactccacc tcccgggttc  93780 

aagcgattct cctgcctcag cctcctgagt agctgggatt acaggcgtgc gccaccatgc  93840 

ctggataatt ttgtattttt agtagagacg gggtttctcc atgttggtca gtctggtctc  93900 

gaactcccga cctcaggtga tccacccgcc tcggcctccc aaagcgctgg gattacaggc  93960 

gtgagccact gtgcccagcc tgcagcatgt attagtactt tgtttctttt gggggtaata  94020 

ttccattctg tatatatact acaatttaac tgttcatctg ttgatggaca tttatattat  94080 

ttccatgtat tggttaaaat gaataatgct actataaaca attgtgtaca aatttctatg  94140 

tggacttaaa tgttttaatt tctttccttc tttcttgggg aggagacggt ctcactctgt  94200 

cacctaggct aaagtacaat ggtgcaaaca cggctcattg caacttcgac ctcccagacc  94260 

caagtgatcc tcccacctca gcctcccaaa tagctgatac cacaggcatg catcaccatg  94320 

cctggcttat tttttctgtt tgtttgttgt ggtagagatg aggtctccct atgtagccca  94380 

gccaggctgg tctcaaactc ctaggctcaa gcagacatcc tgcctcagcc tcccaaagtg  94440 

ctgggattat aggtgttagc ctctgcacct ggctgtgttt tcatttttcc tgggtatata  94500 

tttaggaata aaattgttga gtaatatggt aactccatgt ttaatttttt gagaaactgc  94560 

caaactgttt tcctcacaac tgtaccattt tatccagcaa tagtgagagt ccctgttttc  94620 

ttcacattct ttctaacaat taataattat tttattattt aaagctttcc tagcaggtat  94680 

gaagtagtac ctcatgcttt tgatttgcat ttctttaatg accaatgata ttgggcatct  94740 

tttcatgtgt ttcttggcca tacgtatagc tttttttttt tttttttttt tgagactgag  94800 

ttttgctctt gttacacagg ctggagtgca atggtgcgat ctcagctcac cgcaacctct  94860 

acctcccagg tttaagtgat tctcctacct cagcctcctg gcctcctgag tagctgggat  94920 

tacaggcatg caccaccaca gccagctaat tttgtatttt tagcagagac gggttttctc  94980 

catgttggtc aggctggtct cgaactcctc acctcaggag atccgcccac ctctgcctcc  95040 

caaagtattg ggattacagg tgtgagctac cgcgcccagc cgttgtatag cttttttaaa  95100 

gaaatatcta ttgaaggtgc cgattttaaa attaggttgt caggccgggc acctcaggag  95160 

gctgaggcag gagaatcgct tgaacccagg agggggaggt tgcagtgagc cgagatcgca  95220 

ccgctgcatt ccagcatggc gacagagcaa cactgcatct caaaaaagaa aaaaaaaatt  95280 

agccaaatgt ggtggcacat gcctgtattc ccagctactt gggaggctgt ggtgggagga  95340 

ttgcttgatc ctgggaggca gagccaagat tgctccactg cactccagcc tgggtgacag  95400 

agtaagacct tgcctcaaaa aacaagtaaa taaaagactg acattcctat ttatgtagat  95460 

aagttcattt tttctcattg tactgtattt accaaataaa tttaagacaa aaatgccctt  95520 

ttttatagag taacacagca tctggtggaa tgacacgacg aaatacttat gtttgcagtg  95580 

agagaactac agctgataga cactcagtga ttcagaatgg caaagaaaac aggtaggaga  95640 

ttctacctgt ttgtaagaaa agttgttttt cccaagagaa atggaagcat gttatttact  95700 

gctttgttct tataatcatt ttcaaattaa aactgtaagt attctctgaa ggtaagttaa  95760 

atttgtatac taatttttag caagatacta gaattctaaa ttctttttgt tgtccagagc  95820 

atcatcctcc tgcctggctg tgtatgatga ttaaaaggct tgagttaaac ccagggggtt  95880 

tcctagagga agtagatagt aagctgtggt tatgttgtag aacagtgaat aaggaaatgg  95940 

agattgtctt gtgctcatta ataacttgaa caaaagccga aagtggggga agataaggac  96000 

gtgaggcaga gagtcatacc tcaggagaat gtacagcacc aggtagcatt aaaggtccgc  96060 

agtttaccaa agggtccaga tggctgagtc taaatagaaa cactggagaa gccaagagaa  96120 

gtggaaagtc cagccttctg aatgctttta atttggctac atagcaagca tacataggat  96180 

gagcgtgact ttaaaaagac aatgatgtta catgtcaata aggagagcat cctatcatgc  96240 

acatgatttt cttggggttt tgaaataaaa taagtagagt cagtaaaatg ggattggata  96300 

ggtgtagaga ctctgaggtg gggttagtct gggtggagag aaaagagaag ttagattggt  96360 

agagaatagc taaatatgct atattctgtt cagaacaaat ttcccaggct ggcatggatt  96420 

ttccttcttt gtttttggaa gagcagtaag tgtacatcat tcttttaact tgaacattgt  96480 

ttgcatcaga attgttctga catttacttt ctgcagttac ggtgtgaggt tctgtttctt  96540 

aatcctaacc tatgtttgat ctcattagtc aaacaaaatg tttgatcact acattttgtg  96600 

acagcctaat caaaaattct ctcctccttc atccttagtt ccaaactgct tatcacttcc  96660 

ctgttccata ggccacttag gattgagttg atatgaggag taacatttgt tctgtaagat  96720 

tatggttatt attcgttgaa tttttagcaa tatttacatt ctcttgttct cttttatgac  96780 

tcgtgtgtgt gtgtgtgtgt gtttcaacat tgtcttttct tatgattaaa aactactaag  96840 

aacttgagta tagcagctgg ggtagatagt ttacagataa tgattgatat aggtatttct  96900 

tttttttttt tttttttttt ttttttgaga cagagtctca ctctgtcacc caggctggag  96960 

tgcagtggcc tgatctcggc tcactgcaag ctccgcctcc cgggttcacg ccattctcct  97020 

gcctcagcct cccgagtagc tgggactaca ggcgcctgcc accactccca ggtaattttt  97080 

tgtattttta gtagagacgg ggtttcacca tgttagccag gatggtctcg atctcctgac  97140 

cttgtgatcc acccacctcg gcctcccaaa gtgctgggat tacaggcgtg agccaccgta  97200 

cccagccagg tatttcttaa tagtagtcta ctctctggta gatttgtatt atagttcagt  97260 

tcttaacttt caaatttctt ctagttcaaa agtgacttaa tagaaaatat caatagaaga  97320 

cttaattaga agtttctggt gttacagatt gtagtctaca ggactacaga aatgtttcat  97380 

ggtcaggcac agtggctcac acctgtaatc ccagcactct gggaggccaa ggcaggtgga  97440 

tcacttgagg tcaggagttc gtgaccagcc tggccaacat ggtgaaaccc cgtctctact  97500 

aaaaatacga aaattaacca tgtgtggtgg cacgcgcctg tagtcccagc taccagggag  97560 

actgaggcag gagaattact tgaacccagg aggcagagtt tgcagtgagc tgagatcgcg  97620 

ccactgcagt ccagcctgga caacagagca agactcatct aaaaaaaaaa aaagttgttt  97680 

cattaccttt actacttcta aattctgaaa atgcactacc cagctccttc tgaactttag  97740 

gatatgtgac tgtctgaggt gcagagtcag tctcctcaag ggtgttaaga ctaagatctg  97800 

ctctctgctt ccatcctgtg ctacacgtat catacaccag gcacatgcat atatgcctgt  97860 

gtcttctgat tctcttttcc taaaattttt cgtttcactc tttggaaata atatttaaga  97920 

cttctttaat ttctttggca atatttcctt tctgcattcc ccctggagac acctgccttg  97980 

ttggggccaa ctctttcata tcctgacctg tctcgttgct tctcttagca tcagtcattg  98040 

aaatactttg cttctgaagg tgtcgtcttt ctctttagtc aaagagagtc tcaccgccaa  98100 

accttaaaag acagggccca ttgttttaat aatatttgga ctttcctttc ctatcttata  98160 

aatgaattaa aagactggaa aattattggg tttaacttct ttagttaagg cactaaatgt  98220 

gacagctttc ccttaaaatt gatgcttgag tcttcagtga gatacaatta gctttccctg  98280 

cacagatgac ttcttcggca aattgttcct tttccctctc ttcacccacc catatatctt  98340 

atttcttcac taatttaaaa tatgagtgag ctgtaggatg cctggaccta tgttaacttc  98400 

tgaaacaaac atgttaagtt ccaattttag ccttaaatat tttcgacatt tagccttaaa  98460 

tgttttcttc tttatatgag tgttcatacg gaatttcaac atgagaataa tgatggctga  98520 

ttttttaaaa actgtgtgaa ggtttaaacc agagactcca catatcttaa gcccttacta  98580 

ccttcaaaat cctactgtaa acaggatatt ttaaaggctt actaaatgca aggctttttc  98640 

tcgtcatagg caatataatt aattttaatt attttttctt ttgaaaatta gttttattaa  98700 

ttggttctta ctaggccaat ctttgtttta tcagctttcc tgtgggaaca ataaagttaa  98760 

tgacacaggg agcataggtt agggccagtt gttactttgg cacaaacacc tgtgattcgt  98820 

tttctgagac tagttttaaa ctggtcgtgc tgaaggccag cccactttct gctgtaatta  98880 

ttctgccttc tgatgttatt ctcgaaaaat ggccagattc caggcgtgac taatggttgg  98940 

tgtaaactag gcatgagaag gtttgattac accttcaatt gtatgattct atcatgatgg  99000 

tataggtttg cagtgagtct taaaccacat agcactgaca cgtagtgagt gctcaaacaa  99060 

atgttagctt tcattattaa ttatagactg ttcagacaag gttatgcaga attttcttag  99120 

tttgcactga ctaaacctaa tctttcaagt taataatgtt gctaaaccac ctacatagca  99180 

gagacactct gctcctacga tttcatatgc tttagatacc cggacgacac tgtttagact  99240 

acttcattta aagaccccag agaagtgacg tgctggtgtt acagtaatgc aaacagaatc  99300 

ttttcttttt tttttttctt tttttctttt tttttctgcg atggagtctc gctcttttac  99360 

ccaggctaga gtgcaatggc acgatctcgg gtcactgcaa cctccatctc ccgggttcat  99420 

gcagttcttc tgcctcagcc tcccagtagc tgggattaca ggcacacacc accacacctg  99480 

gctgattttt gtatttttaa tagaaatggg gtttcactag gccaggctgg tctcaaattc  99540 

ctgacttcaa gtgatccacc tgccttggcc tcccaaagtg ctgtgattac aggcatgagc  99600 

cactgcacca ggcccagaat ctttcaaata aattttagat attggatatt actgtaaagt  99660 

ttcaaaattg tgaagtggct tattatttta tccactttac cctgcatcaa gtcacataga  99720 

gattgagcag agaaggattg aggacactta gcgtatgtat ctttggacta catataaaag  99780 

ttgctttttt taggctgggc gcggtggctc ccacctgtaa tcccagcatt ttaggaggct  99840 

gaggcaggtg gatcatgagg tcaggagatc aagaccatcc tgaccaacat ggtgaaaccc  99900 

tgtctaaaat taattagctg ggcgtggtgg catgcgcctg tagtcccagc tacttgggaa  99960 

gctgaggcag gagaatcact tgaacccagg aggcagaggt tgcagtgagc cgagatagcg 100020 

ccactgcact ccagcctggc aacagagcaa gactctgtct caaaaacaaa aaaaaagggc 100080 

tgagcacagt ggcttacgcc tgtaatccca gcactttgcg aagctgaggt gggcggatca 100140 

cctgaggtca ggagtttgag accagcctga ccaacatgga gaaaccccat ctctactaaa 100200 

aatacaaaaa aaaaaaaaaa aattagccag gcatggtggc gcatgcctat aatcccagct 100260 

acttgggagg ccgaggcagg agaatcgctt gaacccagga ggcagaggtt gcggtgagcc 100320 

aagattgcac cattgcactc cagcctgggc aacaagagca aaaccccatc tcaaagaaaa 100380 

aaaaaaaagg ctgctttttt tttttttttt ttttttttaa gatggatgga gtcttgcagt 100440 

gtggcccagg ctgcagtaca gtggctagtc acagacatga tcatagtgta ctgtagcctt 100500 

gaactcctgg gctcaaatga tcctcctgtg ttggcttctt gagtagctgg gactacaggc 100560 

atggaccacc acacctggct aattttttat tttttgtaga gatgaagtct tcccatgtta 100620 

cccaggctgg tctcaaattc ctggcctcaa gggatcctcc agtctcagcc ttccaaaaca 100680 

ctaggtttac aggcatgagc caccatgcct gtccttggac tatattttta attctgcttt 100740 

tgcccagtca cttgagtatg cttttaatca gcagccaata catttcttat cagaatgttc 100800 

tgataggggc tagaggtcat agcaacaaat tcaaagtgcc tatcctttag taaccttaag 100860 

tggattaatg ttttagaaaa gatagtcaag actgggcaca gtggctcaca agccctgtca 100920 

tcccagcact tcgggaggcc tagacaggaa gatcacttga ggccaagagt tcaaggtcag 100980 

cctggacaaa gtagcctgag acccccgtct ctataaaaat atatatattt tttaatttta 101040 

aaagatagtc atgaatacaa aacagttggg aagattaata ggaactctct tcatgcaact 101100 

tgaattttaa gaaaaacatt gctatttcta tcaattaagg tttaaatgta gaccaggcat 101160 

gatggctcac gccaccatgt aatcccagca ctttgggagg ccatgacagg aggattgctt 101220 

gaacccagga gttcaagacc agcctgggca acatggtaaa attccatctc taccaaaaat 101280 

acaaaaaaat tagctgggtg ccaggcacag tgcctcacac ctataatccc agcactttgg 101340 

gaggccgagg caagtgcatc acctggggtc gggagttcaa gaccagcctg gccaacatgg 101400 

tgaaacccca tctctactaa aaatacaaaa attagctagg tgtggtggta catgccggta 101460 

gtcccagcta tttgggaggc tgaggcagga ggatggtttg agcctgggag atggaggttg 101520 

tagtgagccg agatcacacc attgtattcc agcctggacg gtagagccag acccagtctc 101580 

aaaaaaataa aaataaaaaa attaatgtaa tacagctact atgaacccac aaaaacttta 101640 

aaaaaatttt ttaattatta aaaaaatgta atgctgctac tgttttgctt atgtagattg 101700 

tgggctagaa taggaaataa aactatcatt tttaacactt ttctgggggg aaatattatt 101760 

cgaatttcat aacaattagc ttgatgacct tttagaatat atatgtagac cattgtgatg 101820 

ttggggctgc ctgttgtaaa taggattttt gtgagcttga ttgtacaaaa ttgaaatttg 101880 

caaacatctt actgagttta ctgtttcctt ctgggtgtta ggcctactgt agaaatcaga 101940 

aaaatcggaa atattttgtt gcttgctttg tgaaactcat gatgtgacat ggattaaatt 102000 

tctaaaaagt ttatttaatt gcctttaaaa ttagtatgtc aaaaagttta tttatttatt 102060 

tatttattta ttttaatttg aaacagtctc tctctgtcac ccagactgga gtttagtggc 102120 

atgatctcag ctcactgcag ctaccacccc cgggtttaaa cgattcttat acctcagcct 102180 

cctgagtagc taggattaca ggggcccgcc accacaccca actaattttt gtatttttag 102240 

tagtgatggg tttttgccat gttggccagg ctggtctgga actcctggcc tcaagcaatc 102300 

cacccgcctc agcctcccaa agtgctggga ttacaggcgt gggccaccac gcccagcctc 102360 

aagttaataa tttataatcc cagcactttg ggaggccaag acgggcggat tgcctaagct 102420 

caggagttcc agaccagcct gggccatgac gaaaccctat ctctacaaaa tttttttttt 102480 

taatttataa tgagaaaata aatttacatt tccttcttag gtctctagag gatccatttt 102540 

ttttctgcaa agcatctgtc cacaccctct taccatgctt gtatgcctta aagatctagc 102600 

ttggcctgtc agcagtgtgc ttcattggga atcgatgcag caccctcctg cctgcaagct 102660 

gactaaaagc cttttccttc tccaaagact ttgggaccat ttgtattcac cagggaaagg 102720 

gtcaaacaac tcctgcatct tcttcccctg cttttcttgg cacatctact gatactagct 102780 

cctaatttgg gcaagaaaaa agtcaacaac tggaggtaga gtgtgttgac cctggactca 102840 

ccctgaaagg taagggcaca agagatagtt gtatttagct gtatcttgtt agaaaaatac 102900 

atttgtgtag ccaggcgcgg tggctcacac ctgtaatccc agcactttgg gaggctgagc 102960 

cgggtggatc acgaggtcag gagttcaaga ccaccctggc taacatggtg aaatcccgtc 103020 

tctacgaaaa atacaaaaaa ttagccgggc gtggtggtgg gtgcctgtag tcccagctac 103080 

ttgggagact gaggcaggag aatggcgtga acccaggagg cagagcttgc agtgagcaga 103140 

gatcacactg cactccagcc tgggcgacag agtgagactc cgtctcaaaa aaaaaaaaat 103200 

aaataacatt tgtgtgcatt catgtgtacg tgtgtctgta cacatgtaca agaaacaacc 103260 

gagcatttct ttaaaaacct tagtcagtta gaactgtctc tgttgcaggt gacagaaaac 103320 

ccagtctaaa caggcttaaa tataaaaggg ctgttagttc atataactaa aaaaagtcca 103380 

gggctagagt tacggtccat ctgcttctgc ctccttggcc gtagttccat gattgggctc 103440 

ggcaccatca gacataactt cttcccacac acagctgtgc tcaagcagaa gccctcaggt 103500 

ggtctccttg atctgtgtgg ggcctagagt tacttccacc acagcaaaat ctcattattg 103560 

ttgctgcagg aaaagaatgg atactgagtg gcagaaatac gaaactggat aaatttttgc 103620 

ctttataaga catttgtttc cagtccttct cagactgtat aaattctccc aagtcagaga 103680 

gcagaattct caaacaaaaa tgcagggaca gaaccaggca cagtggctca caaggcctat 103740 

aatcccagca ctttgggagg ctgaggcaga aggatcagtt gaacccagga gttcaagacc 103800 

agcctagcca tcatagtgag acaccatctc tacaaaaaat ttaaaaatta gccaggcata 103860 

gtggcacact cctgtggctg agataggagg atcgcttgac cccaggaggt tgaggctgca 103920 

gcaagctgtg atagtgccac tgcactctag cctgggtgaa tacagcaaga ccctgtctcc 103980 

aaaaataaaa atttaaataa aaatgtttta attcagggac aagcagttct tgattttaaa 104040 

gacgtatctg ctttatgttg gggctatcag aattccagtt gctaattgat taatctgctc 104100 

tgttaggaga acgtttgttg aatacctgcc ctgccaggct ttctgcttac actggtgggg 104160 

ggcacattga caagattttg ggctgtgttt tcagggacct ccagcagaga agggtcacta 104220 

ggatacaatg tggcatgcat gagctaaaaa cagaagtgat ttaactctca gagggaaaat 104280 

ggatcagata acacttcata gagatgacga catctggttc atttttgaag agtgaataga 104340 

aagatcccag ccctccatac caagagaata actcctgcaa acattttctg acctggtgcc 104400 

tgaccaatgg accacacatc atcaggaagg ctagaaagtt gagttccagg agggaatgat 104460 

agaaggcaaa gcctagagag atggcagggg ccagacttca ggggcctggg gatgtgtact 104520 

tgcactccaa gtcgaggaga ctgaactttt taccaaagac ttggtgttct gtagaagtat 104580 

gagcagatga gtgacaagat ctggtttata tgttaagaag ttctcagctg taaggtgaat 104640 

agattggagg tgttggggca aaggcagggg acccagtgaa gacaaggagc gaggctctat 104700 

actgaggccc tggtagaagt ggagcagatg ggccacctga agagctacta ggaagttgac 104760 

accaataaga tgtcgttagt ctgtgtatgg ggagtgaggg aaaggaagaa cttgccagtt 104820 

tccaggtttt aatccttcca aaggatttct gcagaaagac actggaagag ctgtattcct 104880 

acttatcctt aaaggaaaga aactgccctt gaattccaag gacatgatta ctgagctgga 104940 

attccaaata atgtgtccca gtgagactcc tgggggtagt tttgtccggt aactgtgtgt 105000 

gttagatgaa actgcagact tccagccact ctatcttacc atgtctgtta acagttaatt 105060 

tgctctgatg aatttgccca tcttggagaa gggggctctg ctgactgttt tttatcttgg 105120 

agtaaatgtc ctttgattag gaaggttcta gactatattg ttaaaacaac attggaaggc 105180 

tgggcatggt ggctcatgcc tgtaatccca acactttggg aggccaaggc aggcgtatcg 105240 

tttgagccca ggagttcaag accagcctgg gcaacatgac aaaactctct ctactaaaaa 105300 

tacaaaatta gccaggcatg gtggagtgcg cctgtattcc cagccactta ggaggctgag 105360 

gtgggagaac cacctgagcc caggaagttg aggctgcatt gagccatgat cgtaccactg 105420 

cactgcagct aggtgacagc aaaaccctgt ctcaaaaaaa caccaaacaa cataggatac 105480 

tgttatataa cagctagttc ctatacctgt aatcttatta attcatttaa aatacatcag 105540 

tgcgggccgg gtgtggtggc tcacacttat aatcccaaca ctttggaagg ccaaggcggg 105600 

aggatcactt gaagccacaa atttaagacc agcctggata atatagcgag accctgtctc 105660 

tacaaaaaaa ataaataaag aaaaaataaa atatgtcagt gtgttttggg aacaggttga 105720 

gagcatagca tgctcatatt atatattcat tttaccactt agatttgaat tgaggcatct 105780 

cttagaatag gttttatttt gtgcataccc tcagaggaca ttgtccctct catagaaaca 105840 

gatattcaaa catgtaatct gctattttat tttaaggtaa tagattttta tgattactgt 105900 

ttggaaaaaa aaaaaagcaa ctataggtta gcagttgctc cagaatctcc aaaacaagct 105960 

taggagattt ttattcttta ccagaaatga gatggcttgg gaggaaggtg tgtgcattac 106020 

acacaggttg ctctgtggtc actgctcctt catactgtgt ttctgcctct gcctgaaccc 106080 

aaacccctcc cagcctgaca gaaatgttcg cttacgcagc tagccctgcc tcagtttgta 106140 

catctacctg tcggctgaga catcagaagt cgatgtccat gtcagcctct gggcacccca 106200 

agatgatgtt acctccaata gacagtgaag gagataactt caaggctatg taagaaaaat 106260 

gcacattctt tgtgaaacta atgtgtaccc actgcttctt aattttgtgc tgtggatttt 106320 

atagtctgag attttgttac agttgtccac aaggcgtcct tcctccatgt gattttagtt 106380 

aagcacatct tttgtcatga tgtcctcggt tgtgtattgt gtgtcttcgt gccttcgcgt 106440 

actacaaaat gtataagaag ttcctgctcc tcccaagttg ctttcagcat gtggaatttt 106500 

atacatatat catttgttta cttccaaaac tttttagttg cctgttcttc agttacgcca 106560 

gcatatcctt tatttctttc gtattggcac agttctctat gtaagcaatt tgagagggaa 106620 

gcaaagggga aaagtttgag ttagctgttc tctgtcctag aatttccctg cattaatctt 106680 

gtccttgaaa atatatataa tactggtccc ttaaactcca tgaggctttg tctcattatg 106740 

tattgttctt ttggtaccct ttcccactta acttaccttt tgctcctaag tcctataaaa 106800 

taccccttgg atctggattt tttatacccg attttctcca ctgtgtataa aaggtatatt 106860 

gtgactgtaa atttttgtat atcatgttct gagagcttct tactttctga tctcatagca 106920 

ctattcctga tcagagaact ccagttgctt caacacacag tatcagtagt gcagccaccc 106980 

cagatcgaat ccgcttccca agaggcactg ccagtcgtag cactttccac ggccagcccc 107040 

gggaacggcg aaccgcaaca tataatggcc ctcctgcctc tcccagcctg tcccatgaag 107100 

ccacaccatt gtcccagact cgaagccgag gctccactaa tctctttagt aaattaactt 107160 

caaaactcac aaggaggtaa gtgctaggtg ctggttgttt tggagtgaac acatagagca 107220 

aaaggaaaga tgtctttttt gttgtgtgaa gccactgcta cctggatgct tttcagtctg 107280 

ccttcagctc atggttttct ggttttatat atatctaact ttatacttta aaacctttaa 107340 

agtagaaatt gtagagctca gagtcttcat aacactaaaa gttaactagc atttaggagg 107400 

tttttgttac tgttctttaa ttattgttcc ttttgctcac gtatctgtct gcatggcatg 107460 

ttcgttgttg ttgagcaggc agacctcgag ttctggtgtg gggtgggggg ctggcactct 107520 

gtaacaatca gcaggaaaga ccatgcatgt ctttcataat catctccagc cccagaggaa 107580 

agagacagct tctcttttct cactttattg ttgttaagga gcagtaaatt tcttaagagt 107640 

ccaaatcttg aaagtttctc tctcagtctt agtaatttat attgagagca aggtaatgtc 107700 

cttaaatggt atagttttgg agataaaatc tctggtttat tatcaaaaaa taatgttact 107760 

attattaagt tatttttatt aaatgctgca tgattcttgg ctgatggtcc tggaaatttt 107820 

ttaaaatgtt ccatgtgtct agtaggctag catctggggc ctcagtaaac tctcaagggt 107880 

cctttgagat taacttcatt tccgtaacct tgttacctgt tacaaaagcc cagaaatact 107940 

ggctgcttca agaggaaaaa gaaaggatac cactttgaac cgtaaacaat agtgaaaggc 108000 

acctttccga gaaggagccc aggaaaccca agagcccctg cagtttcagg acatccttgg 108060 

agaaatgttt tgaaattaag cctagctgtg gatgagtctg tctgtggtat cttgcaggtt 108120 

tgcctaggac ggaccctctt atttgtcatc tgtagcttac aggacagcag taggagtctt 108180 

tcccgagtct gaaatgatca gtaccctcct ctgtttttct gcattcccta tggcctatag 108240 

cctattactt catttcactc catctccatt atttaaacta agctaaatgt aatcttgtat 108300 

tcgatcatct gaaacttcgg tgagtcacat taaagtctga tctacttatt attaggacat 108360 

ggaatagatt agggagtatt cctttttttt ttttttttaa tttttttttt ttttttgaga 108420 

cggagtctca ctgtcgccaa ggctggagtg cagtggtgca atcttggcta acttcaacct 108480 

ccgcctagat tagggaggat ctctgacatc cattagcatt aactagaagt cagacgcatc 108540 

agaaggtttc tatttaccct cttactcact tcttagcccc tttattaagc cacctcattt 108600 

taaactgggc aaaacagaat cagccaaaga gctttgccag gtttgggaca cccattcatg 108660 

accagccagc aagagagaca gtgagttcaa tctgagaaga gtctggtgac tcccagaata 108720 

aaccattcct tcctggccag ccgtggtggt tcatgcttgt aatcccagca ctttgggagg 108780 

ccaaggcggg tggatctcct gaagtcagga gtttgagacc agcctgacca atatggtgaa 108840 

accccatctc tactaaaaat acaaaaatta gccaggcatg gtggtgggcg cctggagtcc 108900 

cagctaccca ggaggctgag acaggagaat tgcttgaacc cggaaggcag aggttgcagt 108960 

gagccgagat cgtaccactg cactctagtc tgggtgacaa agtgagactg tgtctcaaaa 109020 

aaaaaaaaaa aaaaactttg agtttatttt tcttctttgt actctttttt cagtcatttt 109080 

aagactagta ttgggctggg ccggatggct catgcctgta atctcagcac tttgggaggc 109140 

caagaggggc ggatcacctg gggtcaggag tttgagacag gcctggccaa catggcaaaa 109200 

ccccatctct actaaaaata caaaaattag ccaggggtgg tggcgctcgc ctgtagtccc 109260 

agctactctg gaggctgagc caggagaatc gcttgaacct gggaggcgga ggttgcatct 109320 

agccaagatc gcgccgctgc actccagcct gggtgatgac agagcgagac tccatctcaa 109380 

aaaaaaaaaa aaaaaaagac tagcattgat tggccaggca tggtggctca cgcctgtaat 109440 

cccagcactt tgggaggccg aggcaggtgg atcacctgag gtcgggaatt tgagaccatc 109500 

ctagccaaca tggagaaacc cagtctctac taaaaataca aaattagccg ggcatggtgg 109560 

cacatgcctg taatcccagg gagactgagg caggagaatc acttgaacct gggaggcaga 109620 

ggttgtggtg agccgaggtc acgccattgc actccagcct gggcaacaac agtgaaactc 109680 

tgtctcaaaa aaaaaaaaaa aaaaaaagac tagcattgat tttattacat gtatataatg 109740 

gaaaaaagga aacaagatta tcattgataa aaatatcagc tacctctttt tttttcccca 109800 

cagagtctca ctttatcgcc caggctggag tgcagtggca tgatctcagc ccatggcaat 109860 

cttcgccttc caggttcaag tgattcctgt gcttcagcct cccgagtggc tgggactaca 109920 

ggcgcccacc atcgcgcctg gctaattttt gtatttttag tagagacccg gttttatcat 109980 

gttggccagg ctggtcttga actgctgacc tcaagtgatc caccgcgccc agccaaagct 110040 

accattattt gaatgcttat tatgtgctaa ggtagatgtc tatatacata gatacagtca 110100 

tattcatttt atacatataa atatgtatgt acattatata tatgcatatt ttatgtataa 110160 

aatgagtatc atatatatac acttatatgt gtgaaatgag tatatttata cacatgtaca 110220 

agtgtgcaca cacactcatt taatttaatc tccatagtcc accccatttt gtaaaagaaa 110280 

ctgaaggtga agtttggaga gattaaggca catattttaa aaagtatcag ggcctggtgc 110340 

agtggcttac gcctgtaatc ccagcacttt gggaggccaa ggcaggtaga tcaggtagat 110400 

cactcaaggt caggagttca agaccagcct ggccaacatg gtgaaacccc atctctacta 110460 

aaaatacaaa aattagcttg atgttgtggc acatgcttgt aattccagct atttggaagg 110520 

gtgaggcaag aggatggctt gaacccagga ggcgtaggtt gcagagagcc aagatcacac 110580 

cattgcactc cagcctggcg acagattgac actccatctc aaaaaaaaaa aaaagtatca 110640 

ggctgagcca ggtctatctg accagactct gcccttttag ccactacact gtgctccctt 110700 

tagaaaaaac agttgcaggc gtgacagttg cattacattt atttcatata tttgaattaa 110760 

aattggagac tcaggcttgt tgtttaaaaa aattctaagt ggtcatcttg tttacaattt 110820 

ccaggctatt tccacacccc cagatttttg cagaaagata gtcttttatc ctgtcttgtt 110880 

aaagtttatt aactgaggtc tgttgtctcc cttagtgcta tacttaatca gctactgaca 110940 

gtttgttctt aaaaacaatc aaaatccttg ctagagtggt tgaaagttct tatcctcctt 111000 

tagcaataat tggtaggatt aaaattgcat tgcctgaaag gctgaggtgt ttgcacttag 111060 

atgctgcaag ggagacctgg tgtggccagg tctggagagg gctgcagtca ggaagcctgc 111120 

actctgcttg gagagcacat ggctttggag agctatgggc tatttgtagt cgggagcaaa 111180 

actctctctc cttaggatca ggcctggcct tgctcagaga ctgcagagtc acccataccc 111240 

tgcaggcaga acagccaggc acacgcaagt gcctctgccc tcaggttgat ccatgttgcc 111300 

atgggcagtg tgaaggcctc ctcctgcagc tgcctccttc ctctttatac ctcaagggat 111360 

tataggagga aaagttaaga aaagcacttc tatagtaatt gaccagtaac cctgattttt 111420 

ccggtggaag attaggaaat gtccaggcac catggctcat gcctataatc ccagcacttt 111480 

gggaggctga gccacatgga tcacttgagc ccaggagttc aagaccagcc tggacaacat 111540 

aatgagaccc catctctact tttttttttt ttgagacgga gtctcgctct gtcacccagg 111600 

ctggagtgca gtggcacgat cttggttcac tgcagtgtct gcctcctggg ttcaagcgat 111660 

tatcctgcct cagcctcccc agtagctggg actacaggtg catgtcacca cgcccagcta 111720 

atttttgtat ttttagtaga gacagggttt caccatgttg gccaggctgg tcacaaactc 111780 

ctgacctcaa gtgatccgcc cacctcagcc tcccaaagtg ctgggattac aggcatgagc 111840 

caccacaccc agccttttat ttttttaata aaaagaaaaa aagttgggaa atgggccagg 111900 

cactgtacat ggctcatgcc agtaatcctg acactttggg ggaaggtgag gcaggaggat 111960 

catttgaagc caggagttca aggctgacct gggcaacata atgagacccc catctctaca 112020 

aaaacatttt ttaattagcc aggagtggtg gtgcatgcct gtagtcccag ctacttgaga 112080 

ggctgaggca ggaggattgc tcaaacccag gagtttgagg ttacagtgag ctatgatcac 112140 

accactgtac tccagcctgg gtgattgagc aagaccttgt ctctaaataa ataaatattt 112200 

aaaagtaaaa gaaaattagg aaacgaaaat atatcttaaa gacttttaat cattttcaac 112260 

taaaatattt tggataatac tgccttatat ttaggcagta tatattaaag attttcacat 112320 

gcatgattgt actgtcgatg accctgctgt atactactga tctgattatg aagtggttgg 112380 

cagttattta tagtagttag acttttttta aattggtaga ttaataccta aagcaatgcc 112440 

aaagttatcc caaccaagga tttcattaat ttagtcattc agcagatata gatgactgcc 112500 

tgctatgtac agttacagaa ctggacttta caaatagaaa ttaacaaact cagcctattt 112560 

ttgcccaggg aagctgatcg cattgatcat aaaaacctca ttcgtagttt gaaaaatatt 112620 

ttgtcagatt attttcagca caacctgcac atctccttaa atttttttaa tgaccagagt 112680 

tacccctttt aaatagaatt cttcgtgttt actacataaa agtaaaattc atactgttgt 112740 

cttgacactt agtttttatt cattttgaga tctaagactg aaaagtctac ttgtttaaat 112800 

ccccaatcac ctattttttt cttaaaaagt gatttatgtc ataccactgt agcaaataat 112860 

atgttaatgt ttgtttcatt ttcctgaaag aagtaatgat ttttacttag tggttaaata 112920 

ttttataatg aaatttttaa tgtttatgta ataaggcaag atttttgttc ataaggtatt 112980 

ctgaagaaaa ttgaaaaatg ttttattact agtacattgc aaatgtcttg tcacttcttt 113040 

aacataagac ataaatttta tcttagaaag tgtatctggc cattgcagtg gctcatgcct 113100 

gtaatcccaa cactctggga ggccgaggtg ggctgatcac ttgaggccag gagttcgaga 113160 

ctagactggc caacatggca aaaccctatc tctactgaaa atatagaaat taactgggca 113220 

tggtggcgcg cgcctgtgat tccagctact caggagactg aggcacaaga attgcttcaa 113280 

cccgggaggc ataggttgca ttgagctgag attgcaccac tgcactgtga cagagtgaga 113340 

ctctgtcttt aaaaaaaaaa aaaaagtgtg tccatctgaa gaacttttaa ttacagctaa 113400 

tgtcaatatg tactgctaaa ccttttctta cttttttttg atatattaaa agatcacata 113460 

ctcatttaat tacctgtaat aattttactt tttcaacaaa tgtcagcatt tctttgttca 113520 

ttggccagag aaggaaccct gctttgtttt ttttctttct ctctgtaatt gattagattt 113580 

tctgtttaat ttgtgcgagt tatttttgtt aatttttttt tttttttact taatttcttt 113640 

tagaaacatg tcattcaggt ttatcaaaag gtaggattta tatatacaca tttatttttc 113700 

aatcctcact cccaaatggc tcctgcaatt aacattaggt ttggctttct ggccctgttt 113760 

tttccttata aactaaactt tctgctgata actaaatact taattccttg aaaggaaatt 113820 

gaaaagaaat agattaactc tgtcaggcat tttaaaggga ctatggtacc catgcaacaa 113880 

aaggctgatg catgctctgt gtattttctt tctttggtag aattatttag catccaaata 113940 

attctgtctt catactaata acacttagca tgctcctgtt tgaagaatga gatgctcagt 114000 

aatgttaatg tacaattaat gattatccac aggcatgcaa aaggtaagta ttagttgtgt 114060 

tatttttatt tcactgagga tggaattagc aaaaggcttt aaaatgacag gaaaattagc 114120 

taatacagaa aacaagcata aaattcaaag ctacagcctc atttgatttg gctttttcag 114180 

aaattaaaat gtgaacagct gcgtagcaga aatgttttaa tattttcaga gttgaaagcc 114240 

actttccagc aaccactgaa gaaagagtat ctcattattt ttacttaaag cactacagaa 114300 

agtggtgttc tgattttatt aatatttttt aggccaggca tggtggctta tgcctgtaat 114360 

cccagcactt tgggcggatc acttgagccc aggagttcaa gaccatcctg gacaacatgg 114420 

caaaaccccg cctctacaaa taatataaaa attagccggg catggtggca cgcatctgtg 114480 

gtcccagcta ctcaggaggc tgaggcagga ggatcacctg agccctggga ggtcaaggtt 114540 

gcagtgagcc atgatcatgc cactgtgctc cagcctaggg gagtgagacc ctgcctcaaa 114600 

aaagaaaaac atattttttg atggtgataa tcaagaaacc aaaaatattg ctttcttaat 114660 

gcacacatga ggcaggaaat ctttcctgaa gggctacatt gtacctgtgc ctctcaagtc 114720 

accagaaggc caagctgcag gtcaaaactg cgggaaaagc actttcttcc tgttggcagt 114780 

tccattctat tattattttt taattgatct tcccacttgt ctgatttttc cttggacaga 114840 

acaggtaata actgaatata gaatccagct gatagcctca ttggctttta attggaaacc 114900 

cattatactg tgtggcacaa ttagaaagtg agaataaccc cattctgagg ccgagtgtgc 114960 

tcaggctgaa gagccagcag gagtgcccgc tgtgcgtgcg tggtgtgcgg tgtgtgcagt 115020 

gtgcagcgtg cagcggtatg gcatgcaatg tgtgtgatgt atgcagtgtg cagcatggag 115080 

ctggcccctg tgcacacccc tgcagccttg tggaagaagg tagcgctggc tcagtcaaat 115140 

gagaggaaga gttttcataa gcccggctgg tgtttaaaac gtgttttggc tttgttcatt 115200 

ttatggtgtt ggtgttggta ttggtggtca tgtactggca tgtaagattt cttttctctt 115260 

tccctcttct ctctgcttct acattctgtt cattgaggct tccaactgaa tatgagagga 115320 

acgggagata tgagggctca aggtgaggga aatgattttt acttaaaatt tttttcaggt 115380 

gtttacttca tttctgtggc agaggcgact attttctgaa tgttccctac tgtattcctg 115440 

ctgtctctgt aggagttacg tagagagggt ggccacaagg gggcgccagc ctgccatgag 115500 

caccgtccag atccagcttg gcctccgctc tacatttgtg tttgtgttca aagcacggcg 115560 

aggccttcag ccttcctgcc tgggcgttaa cagcctttgg aggtctgggt tgggtagcag 115620 

tgctcagaga aataagccct cagttcatca ctgacccctc acatggttct cttcacaagg 115680 

aataaaagca aagtacttaa tagaatgtcc atatttcaaa ctagatatgt tttcttctaa 115740 

gaatggtgat tatatagttg agtgttttgc ttttcttttt tttttttctg agacacggtg 115800 

tcgctctgtc acccagtctg gagtgtagtg gcgtgatcag ggcttactcg agttcccagg 115860 

cttatgcgat cctcccacct cagcctcctg agtatctgga accacaggca ctgccaccat 115920 

gctggctaat ttttgtattt tctgtagaga tgggggtctc gccatgttgg ccgggctggt 115980 

ctcaaactcc taggctcaag tgaacctccc acctcaacct cccaaagtgc tgggatgaca 116040 

gacatgagcc cccgcaccca gccttgcttt tccattttgt atagttatca ttgcatggat 116100 

ttgaggggag gcaatcacca ggtagcctta ggactctatg tcccttgttc taggtctctt 116160 

ccacttgtgc ccttttttta tgccagtcac cagcaggcta tttcaggtcc tcattcaccg 116220 

tttgtccttt tggtctttct aaaagcccgc ttctggtcat atgacctttc tgaattaaaa 116280 

ccttcagtga cctccactat ttcacctggc cacgtccctg cgaggccctg agtggcgtgg 116340 

tccaggctgc cccagcagcc ccagctctgc tgccccatca aggcagagca ctagggtgag 116400 

tgccaggcag cattccctct ccaggcctac ccatcccagc caggagcagg ctctagatcc 116460 

tggtttgttt ccccacccat aataggaagg tgacataata ggacctacgt gggcatcaag 116520 

taagttgggg cctgaccacc acaagtgctc attaagtgcc accagctgtt gtgggggtga 116580 

tgacactgtg cctccagttc cactcagtct gtgtacttta ttatgccaca gacacatcct 116640 

gtactttcct acctcccctt tggctgtgat cccctctact caaaacaaac actcttccct 116700 

atcttcattg cattttgttg aaatcccatg gctcttcata gctctcctca gatgcaggcc 116760 

cacccccacc cgtgctgttt cctccttgtc tcatcctgcc tgtcacgttc tcctgctcgg 116820 

cgggctccac ctcttctgct gccctctagg agatggccag cctttcctgt gctgccactg 116880 

ttgtctcacc ttacagtctt cctggctcca gatgagtttg agagcttttg cttatctttg 116940 

taacccattt agtatctaac gtggcatttt atacatagga agcttctctc atcagtattg 117000 

gtggatgtga accaaattga atactggcag gttggtgaca cggagagcta tgtgcatatg 117060 

caaaagctgt agcccctcac ctctggttag ttggccatag gatggagtgt acttaaggta 117120 

catagactat tttactccca agaatgctag gcactcactg tcttaattga ggccaccaga 117180 

tacacacatg agaatataaa taacggcttg tggcaataat gactaaatgc caaggagtgg 117240 

ctggtaaacc gcggtgttcc ctagagaccc cggcctgggc tctacttagg ctgcctcttg 117300 

gacatcagac caaggcttac attctgaatc cacagggcat ccacatgggt ggtgtcagtc 117360 

ccccacagac agagaagtgt cccgttgcat ttttccatct attccagtag taagattgtg 117420 

tcatttgaga ttttctttaa ctgtataatt ggacgtttaa ttaacaaacc agagaggagg 117480 

aaaaacaatg aggtgggtag agcatcatgt tcagcctcag ggctgtacag caaagcaatt 117540 

ttagactgcg gatgttgagt ctccagttac cctgagtgcc agttacagtg attcacatct 117600 

gaaagaacag tactgcagga gagggacagc ccagggtgga tgggtggggt gggcaggagc 117660 

tggctggcaa ctccttccct gagctgggcc tgcagagccc tgaggagtgg ggcatgctgt 117720 

cctttttgcc tgatttccaa ggattctgct taacgaatta cttcgttcat tttagtaagc 117780 

acaggtggct ggtgaagatt ttccagctag gtagatcttt ttgtgtgtgg cttatgactt 117840 

ttagggggtg agggaagaaa atagacgaaa atagacttag ttacaaatgt gagtctgtgc 117900 

aggaaaatgt ggaggtcagt cgttagttgt gttgtatcaa agacgtgaat gaggaactag 117960 

ctgaagtgta agaggttgat tttcctgtac gattaaaaat aaacctgcct ctatgcattt 118020 

cagtcgcaat gtatctgctg agcaaaaaga tgaaaacaaa gaagcaaagc ctcgatccct 118080 

acgcttcacc tggagcatga aaaccactag ttcaatggat cccggggaca tgatgcggga 118140 

aatccgcaaa gtgttggacg ccaataactg cgactatgag cagagggagc gcttcttgct 118200 

cttctgcgtc cacggagatg ggcacgcgga gaacctcgtg cagtgggaaa tggaagtgtg 118260 

caagctgcca agactgtctc tgaacggggt ccggtttaag cggatatcgg ggacatccat 118320 

agccttcaaa aatattgctt ccaaaattgc caatgagcta aagctgtaac ccagtgatta 118380 

tgatgtaaat taagtagcaa ttaaagtgtt ttcctgaaca ctgatggaaa tgtatagaat 118440 

aatatttagg caataacgtc tgcatcttct aaatcatgaa attaaagtct gaggacgaga 118500 

gcacgcctgg gagcgaaagc tggccttttt tctacgaatg cactacatta aagatgtgca 118560 

acctatgcgc cccctgccct acttccgtta ccctgagagt cggtgtgtgg ccccatctcc 118620 

atgtgcctcc cgtctgggtg ggtgtgagag tggacggtat gtgtgtgaag tggtgtatat 118680 

ggaagcatct ccctacactg gcagccagtc attactagta cctctgcggg agatcatccg 118740 

gtgctaaaac attacagttg ccaaggagga aaatactgaa tgactgctaa gaattaacct 118800 

taagaccagt tcatagttaa tacaggttta cagttcatgc ctgtggtttt gtgtttgttg 118860 

ttttgtgttt ttttagtgca aaaggtttaa atttatagtt gtgaacattg cttgtgtgtg 118920 

tttttctaag tagattcaca agataattaa aaattcactt tttctcagta aaatcttgca 118980 

ttgtctccta atgctgtatt taacacatcc tcaagttgag cagaagtaat gtgtatgaag 119040 

gcttggggcc acgtggacct tcgcaggggt cccagcattt tgtgattacc agcatatttt 119100 

ttctcccaag gcaataaaga gagaagatgg ccctcatggt gacccaagaa ggaagggaat 119160 

ccagagcagc tgcagcttaa ccctgggagt tgtggcacag ccctatggag aaacaccagg 119220 

tcttgacagt tctgggttgg ttctctgtga agtatgtaaa tttcctttct cctttcttgt 119280 

gattcagtac atgaatcaga cctgcagctt ttgtccaaca cctacatggt tgtgtagggg 119340 

taatgagctc ataactcatt gtgttgcttt attctcacag ggaagttgtc acactgattg 119400 

gtgtgctatt ctgggttctg ggtttgttgt tggtcagagt atgaaagtct ggaggccgga 119460 

cacagtggct cacacctgtg aacccagcac ttttgggagg c                     119501 

 
           
             16  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            16 

gtctcgttca ttcaccgttg                                                 20 

 
           
             17  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            17 

gcgttcagga atatccgcct                                                 20 

 
           
             18  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            18 

gactggcagt gcctcttggg                                                 20 

 
           
             19  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            19 

gagattagtg gagcctcggc                                                 20 

 
           
             20  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            20 

cttgaggtct cgatgtacga                                                 20 

 
           
             21  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            21 

cctcggcttc gagtctggga                                                 20 

 
           
             22  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            22 

ctgcacagga ggctatagag                                                 20 

 
           
             23  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            23 

ttaggattac ttgcattccc                                                 20 

 
           
             24  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            24 

gactcctttt cggatacgcc                                                 20 

 
           
             25  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            25 

ttaattctgc acaatgcgag                                                 20 

 
           
             26  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            26 

tgtaaggata tgtcttgcca                                                 20 

 
           
             27  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            27 

ttctgcacaa tgcgagggtc                                                 20 

 
           
             28  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            28 

ttgaagcaac tggagttctc                                                 20 

 
           
             29  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            29 

atctgcacag gaggctatag                                                 20 

 
           
             30  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            30 

gaaaacactt tacttgctac                                                 20 

 
           
             31  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            31 

aatggtgtgg cttcatggga                                                 20 

 
           
             32  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            32 

gtgtcgagtt taccgccaac                                                 20 

 
           
             33  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            33 

tcgtgtcatt ccaccagatg                                                 20 

 
           
             34  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            34 

ctggctggag caattccctt                                                 20 

 
           
             35  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            35 

ttttggtctg agatgtctag                                                 20 

 
           
             36  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            36 

tagttctctc actgcaaaca                                                 20 

 
           
             37  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            37 

ttttgctcag cagatacatt                                                 20 

 
           
             38  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            38 

cacaggaggc tatagagttt                                                 20 

 
           
             39  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            39 

ccgttctaga tcccgggcct                                                 20 

 
           
             40  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            40 

aaagtgctac gactggcagt                                                 20 

 
           
             41  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            41 

gtgcaaccaa atagtcaaat                                                 20 

 
           
             42  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            42 

cagtgttcag gaaaacactt                                                 20 

 
           
             43  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            43 

cccttgccga ttgttttcaa                                                 20 

 
           
             44  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            44 

cttcttcatg ccctgcattg                                                 20 

 
           
             45  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            45 

cgagctcctg agcggctggt                                                 20 

 
           
             46  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            46 

ttggatttag caccaggaaa                                                 20 

 
           
             47  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            47 

ctgcactact gatactgtgt                                                 20 

 
           
             48  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            48 

agtatttcgt cgtgtcattc                                                 20 

 
           
             49  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            49 

gtgtataaaa tgacccccag                                                 20 

 
           
             50  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            50 

agtggagctt ttcttgcgtt                                                 20 

 
           
             51  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            51 

cattgcgact ccttgtgagt                                                 20 

 
           
             52  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            52 

tagacttgtt ggattcaact                                                 20 

 
           
             53  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            53 

ctagtggaca ttttactgca                                                 20 

 
           
             54  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            54 

ttattgcaac ctctctgcct                                                 20 

 
           
             55  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            55 

ctctgaagag cttttgtaga                                                 20 

 
           
             56  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            56 

tagcatccag ctctgaagat                                                 20 

 
           
             57  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            57 

ctgtgttact actagggaca                                                 20 

 
           
             58  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            58 

atcactgggt tacagcttta                                                 20 

 
           
             59  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            59 

tcggcctaac ctctgaagat                                                 20 

 
           
             60  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            60 

ggttgcacat ctttaatgta                                                 20 

 
           
             61  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            61 

ggtactagta atgactggct                                                 20 

 
           
             62  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            62 

gatgatctcc cgcagaggta                                                 20 

 
           
             63  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            63 

gatgccctta gatgtccggg                                                 20 

 
           
             64  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            64 

ccacccgaga ttgagcaata                                                 20 

 
           
             65  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            65 

gatagctctt tctcgattcc                                                 20 

 
           
             66  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            66 

ggaaaccaaa gtctttgggt                                                 20 

 
           
             67  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            67 

cttgacaacc ctgtctaaat                                                 20 

 
           
             68  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            68 

ctgcagacac aataaatgta                                                 20 

 
           
             69  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            69 

gtttagttaa ccaaacacga                                                 20 

 
           
             70  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            70 

cacctttagg tttagttaac                                                 20 

 
           
             71  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            71 

ctctcagttc ctttggagag                                                 20 

 
           
             72  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            72 

acatgattac ctctagagtg                                                 20 

 
           
             73  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            73 

ccagtatggc atacaaatca                                                 20 

 
           
             74  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            74 

tctgataacc gtaatattta                                                 20 

 
           
             75  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            75 

tgacatgttt ctccttgtga                                                 20 

 
           
             76  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            76 

agttggaagc cttttgataa                                                 20 

 
           
             77  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            77 

ctcatattca gttggaagcc                                                 20 

 
           
             78  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            78 

tgcgacttga gccctcatat                                                 20 

 
           
             79  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            79 

tacattgcga cttgagccct                                                 20 

 
           
             80  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            80 

attgtgttac agcagcaaaa                                                 20 

 
           
             81  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            81 

gacacatttt tgtgcacctg                                                 20 

 
           
             82  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            82 

aatacttcac ctataggtga                                                 20 

 
           
             83  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            83 

gagaagttaa atgatagcca                                                 20 

 
           
             84  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            84 

cagacacaat ctgaatagga                                                 20 

 
           
             85  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            85 

tcggcctaac cttagcaagt                                                 20 

 
           
             86  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            86 

atcacaatgg tctacatata                                                 20 

 
           
             87  
             20  
             DNA  
             Artificial Sequence  
             
               Antisense Oligonucleotide  
             
           
            87 

aggaatagtg ctatgagatc                                                 20 

 
           
             88  
             20  
             DNA  
             H. sapiens  
             
 
           
            88 

cccaagaggc actgccagtc                                                 20 

 
           
             89  
             20  
             DNA  
             H. sapiens  
             
 
           
            89 

gccgaggctc cactaatctc                                                 20 

 
           
             90  
             20  
             DNA  
             H. sapiens  
             
 
           
            90 

tcgtacatcg agacctcaag                                                 20 

 
           
             91  
             20  
             DNA  
             H. sapiens  
             
 
           
            91 

tcccagactc gaagccgagg                                                 20 

 
           
             92  
             20  
             DNA  
             H. sapiens  
             
 
           
            92 

ctctatagcc tcctgtgcag                                                 20 

 
           
             93  
             20  
             DNA  
             H. sapiens  
             
 
           
            93 

gggaatgcaa gtaatcctaa                                                 20 

 
           
             94  
             20  
             DNA  
             H. sapiens  
             
 
           
            94 

ggcgtatccg aaaaggagtc                                                 20 

 
           
             95  
             20  
             DNA  
             H. sapiens  
             
 
           
            95 

ctcgcattgt gcagaattaa                                                 20 

 
           
             96  
             20  
             DNA  
             H. sapiens  
             
 
           
            96 

gaccctcgca ttgtgcagaa                                                 20 

 
           
             97  
             20  
             DNA  
             H. sapiens  
             
 
           
            97 

ctatagcctc ctgtgcagat                                                 20 

 
           
             98  
             20  
             DNA  
             H. sapiens  
             
 
           
            98 

tcccatgaag ccacaccatt                                                 20 

 
           
             99  
             20  
             DNA  
             H. sapiens  
             
 
           
            99 

gttggcggta aactcgacac                                                 20 

 
           
             100  
             20  
             DNA  
             H. sapiens  
             
 
           
            100 

catctggtgg aatgacacga                                                 20 

 
           
             101  
             20  
             DNA  
             H. sapiens  
             
 
           
            101 

ctagacatct cagaccaaaa                                                 20 

 
           
             102  
             20  
             DNA  
             H. sapiens  
             
 
           
            102 

aaactctata gcctcctgtg                                                 20 

 
           
             103  
             20  
             DNA  
             H. sapiens  
             
 
           
            103 

aggcccggga tctagaacgg                                                 20 

 
           
             104  
             20  
             DNA  
             H. sapiens  
             
 
           
            104 

atttgactat ttggttgcac                                                 20 

 
           
             105  
             20  
             DNA  
             H. sapiens  
             
 
           
            105 

ttgaaaacaa tcggcaaggg                                                 20 

 
           
             106  
             20  
             DNA  
             H. sapiens  
             
 
           
            106 

caatgcaggg catgaagaag                                                 20 

 
           
             107  
             20  
             DNA  
             H. sapiens  
             
 
           
            107 

accagccgct caggagctcg                                                 20 

 
           
             108  
             20  
             DNA  
             H. sapiens  
             
 
           
            108 

tttcctggtg ctaaatccaa                                                 20 

 
           
             109  
             20  
             DNA  
             H. sapiens  
             
 
           
            109 

acacagtatc agtagtgcag                                                 20 

 
           
             110  
             20  
             DNA  
             H. sapiens  
             
 
           
            110 

gaatgacacg acgaaatact                                                 20 

 
           
             111  
             20  
             DNA  
             H. sapiens  
             
 
           
            111 

ctgggggtca ttttatacac                                                 20 

 
           
             112  
             20  
             DNA  
             H. sapiens  
             
 
           
            112 

aacgcaagaa aagctccact                                                 20 

 
           
             113  
             20  
             DNA  
             H. sapiens  
             
 
           
            113 

actcacaagg agtcgcaatg                                                 20 

 
           
             114  
             20  
             DNA  
             H. sapiens  
             
 
           
            114 

tgcagtaaaa tgtccactag                                                 20 

 
           
             115  
             20  
             DNA  
             H. sapiens  
             
 
           
            115 

tgtccctagt agtaacacag                                                 20 

 
           
             116  
             20  
             DNA  
             H. sapiens  
             
 
           
            116 

taaagctgta acccagtgat                                                 20 

 
           
             117  
             20  
             DNA  
             H. sapiens  
             
 
           
            117 

tgatttgtat gccatactgg                                                 20 

 
           
             118  
             20  
             DNA  
             H. sapiens  
             
 
           
            118 

ggcttccaac tgaatatgag                                                 20 

 
           
             119  
             20  
             DNA  
             H. sapiens  
             
 
           
            119 

ttttgctgct gtaacacaat                                                 20 

 
           
             120  
             20  
             DNA  
             H. sapiens  
             
 
           
            120 

caggtgcaca aaaatgtgtc                                                 20 

 
           
             121  
             20  
             DNA  
             H. sapiens  
             
 
           
            121 

acttgctaag gttaggccga                                                 20