Patent Publication Number: US-2019177723-A1

Title: Compositions and methods for treating duchenne muscular dystrophy and related disorders

Description:
BACKGROUND 
     Field of the Disclosure 
     The present invention relates to compositions and methods for the treatment of Duchenne muscular dystrophy and related disorders. 
     Description of the Related Art 
     Duchenne muscular dystrophy (DMD) is caused by a defect in the expression of the protein dystrophin. The gene encoding the protein contains 79 exons spread out over more than 2 million nucleotides of DNA. Any exonic mutation that changes the reading frame of the exon, or introduces a stop codon, or is characterized by removal of an entire out of frame exon or exons, or duplications of one or more exons, has the potential to disrupt production of functional dystrophin, resulting in DMD. 
     Disease onset can be documented at birth with elevated creatine kinase levels, and significant motor deficits may be present in the first year of life. By the age of seven or eight, most patients with DMD have an increasingly labored gait and are losing the ability to rise from the floor and climb stairs; by ages 10 to 14, most are wheelchair-dependent. DMD is uniformly fatal; affected individuals typically die of respiratory and/or cardiac failure in their late teens or early 20s. The continuous progression of DMD allows for therapeutic intervention at all stages of the disease; however, treatment is currently limited to glucocorticoids, which are associated with numerous side effects including weight gain, behavioral changes, pubertal changes, osteoporosis, Cushingoid facies, growth inhibition, and cataracts. 
     A less severe form of muscular dystrophy, Becker muscular dystrophy (BMD), a related disorder as described herein, has been found to arise where a mutation, typically a deletion of one or more exons, results in a correct reading frame along the entire dystrophin transcript, such that translation of mRNA into protein is not prematurely terminated. If the joining of the upstream and downstream exons in the processing of a mutated dystrophin pre-mRNA maintains the correct reading frame of the gene, the result is an mRNA coding for a protein with a short internal deletion that retains some activity, resulting in a Becker phenotype. 
     For many years it has been known that deletions of an exon or exons which do not alter the reading frame of a dystrophin protein would give rise to a BMD phenotype, whereas an exon deletion that causes a frame-shift will give rise to DMD (Monaco, Bertelson et al. 1988). In general, dystrophin mutations including point mutations and exon deletions that change the reading frame and thus interrupt proper protein translation result in DMD. It should also be noted that some BMD and DMD patients have exon deletions covering multiple exons. 
     Recent clinical trials testing the safety and efficacy of splice switching oligonucleotides (SSOs) for the treatment of DMD are based on SSO technology to induce alternative splicing of pre-mRNAs by steric blockade of the spliceosome (Cirak et al., 2011; Goemans et al., 2011; Kinali et al., 2009; van Deutekom et al., 2007). However, despite these successes, the pharmacological options available for treating DMD are limited. 
     Thus, a strong need remains for improved therapeutic approaches for the treatment of DMD. 
     SUMMARY 
     The present disclosure is based, at least in part, on the surprising findings that systemic treatment of mdx mice (a murine model of Duchenne muscular dystrophy) with a dystrophin therapeutic in conjunction with a myostatin therapeutic increased, among other things, muscle grip strength in the mice. In addition to increased muscle grip strength, this combined therapeutic approach also increased exon skipping efficiency and protein expression as well as other in vivo and in vitro endpoints over the solo therapy alone. These include improvements in body weight, muscle mass, certain muscle fiber hypertrophy and muscle regeneration, among others. 
     Further surprising findings relate to the age of receptive populations for treatment according to the methods and combinations, among others, described herein. It is generally known that young mdx mice experience greater defined periods of muscle growth and regeneration, and thus tend to have a milder pathology. See, e.g., McGreevy et al. Disease Models &amp; Mechanisms 8:195-213 (2015). By contrast, aged mdx mice exhibit a much more consistent loss of muscle integrity and function, and are characterized by a more severe pathology that is difficult to treat. However, surprisingly, the in vivo and in vitro outcomes noted above were found to occur not only in young mdx mice but also in aged mice as well. This indicates that the compositions and methods described herein would be useful for treating older patients (e.g., pediatric patients seven years of age and older), with more severe pathology and poorer prognosis. 
     Further surprising findings relate to greater longevity and/or survivability in the treatment populations tested. It is known that despite being dystrophin deficient, young mdx mice have minimal clinical symptoms (McGreevy et al. 2015). Severe dystrophic phenotypes that better represent the clinical phenotype, such as muscle wasting, scoliosis and heart failure, do not occur until mice are 15 months or older. However, premature loss of life frequently occurs at this point, as the lifespan of mdx mice is approximately 25% shorter than wild-type mice. Here, however, the inventors have surprisingly found that treatment according to methods and combinations herein provided prolongation of survival in the mdx mice, from at least about 18 to 24 months, well-surpassing typical longevity/survivability in this model. These increased therapeutic benefits and lifespan observed in the aged mdx mice in accordance with the various aspects and embodiments herein is surprising. 
     Accordingly, various aspects presented herein include methods of treating Duchenne muscular dystrophy in a subject by administering a combination of a dystrophin therapeutic agent and a myostatin therapeutic agent. 
     Various aspects include methods of treating a subject with Duchenne muscular dystrophy having a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of dystrophin pre-mRNA. The method comprises administering to the subject an effective amount of an antisense oligomer comprising 17 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides in a target region comprising an exon of human dystrophin pre-mRNA, where the antisense oligomer induces skipping of the exon; where, said oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and where, said subject has been administered a myostatin therapeutic that inhibits one or both of myostatin activity and myostatin expression in the subject to thereby treat Duchenne muscular dystrophy. 
     In various embodiments, said exon is selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. In some embodiments, said exon comprises exon 23. In some embodiments, said exon comprises exon 45. In some embodiments, said exon comprises exon 51. In some embodiments, said exon comprises exon 53. In further embodiments, said exon comprises exon 8, exon 44, exon 50, exon 52 or exon 55. 
     In various embodiments, the antisense oligomer comprises 20 to 30 subunits. In some embodiments, said antisense oligomer is selected from SEQ ID NOS: 76-SEQ ID NO: 3485. In further embodiments, said antisense oligomer is SEQ ID NO: 76. 
     In various embodiments, said targeting sequence is complementary to at least 15 contiguous nucleotides in the target region. In some embodiments, said targeting sequence is complementary to at least 17 contiguous nucleotides in the target region. In further embodiments, wherein the targeting sequence is 100% complementary to the target region. 
     In various embodiments, said myostatin therapeutic is a protein or nucleic acid. In some embodiments, said protein is an anti-myostatin antibody. In some embodiments, said protein is a soluble receptor. In further embodiments, said soluble receptor is ACVR2. In some embodiments, said nucleic acid is at least one of an antisense oligomer or an siRNA. 
     In various embodiments, said antisense oligomer comprises 12 to 40 subunits, and further comprises a targeting sequence complementary to 12 or more contiguous nucleotides in a target region of myostatin pre-mRNA; and where, said oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing. In embodiments, the antisense oligomer comprises 20 to 30 subunits. In some embodiments, said targeting sequence is complementary to at least 15 contiguous nucleotides in the target region. In further embodiments, said targeting sequence is complementary to at least 17 contiguous nucleotides in the target region. In embodiments, said targeting sequence is 100% complementary to the target region. In embodiments, the target region comprises SEQ ID NO: 1. In embodiments, said exon comprises exon 2. 
     In various embodiments, said target region is selected from (i) a nucleotide sequence where at least one nucleotide spans a splice junction associated with intron 1/exon 2 and exon 2/intron 2; or (ii) a nucleotide sequence where no nucleotide spans a splice junction associated with intron 1/exon 2 and exon 2/intron 2. In embodiments, the splice junction is selected from a sequence comprising a splice acceptor site or a splice donor site. In embodiments, the splice junction is selected from a sequence comprising a splice acceptor site or a splice donor site. In some embodiments, the splice acceptor site is provided within SEQ ID NO: 2 and the splice donor site is provided within SEQ ID NO: 3. 
     In various embodiments, said nucleotide of (i) is selected from SEQ ID NOS: 16-43. In embodiments, said nucleotide of (ii) is selected from SEQ ID NOS: 44-70. 
     In various embodiments, the subject is a pediatric patient of age 7 or greater. 
     Various aspects include, methods of treating Duchenne muscular dystrophy, the method comprising: administering to a subject an effective amount of an antisense oligomer of 12 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre-mRNA; and wherein, said oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and where said subject has been administered a dystrophin therapeutic that increases dystrophin expression in the subject to thereby treat Duchenne muscular dystrophy. 
     In various embodiments, wherein the subject has a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of human myostatin pre-mRNA. 
     In various embodiments, the antisense oligomer comprises 20 to 30 subunits. In embodiments, said targeting sequence is complementary to at least 15 contiguous nucleotides in the target region. In embodiments, said targeting sequence is complementary to at least 17 contiguous nucleotides in the target region. In embodiments, the antisense oligomer is 100% complementary to the target region. In embodiments, the target region comprises SEQ ID NO: 1. In embodiments, said exon comprises exon 2. 
     In various embodiments, said target region is selected from (i) a nucleotide sequence wherein at least one nucleotide spans a splice junction associated with intron 1/exon 2 and exon 2/intron 2; or (ii) a nucleotide sequence wherein no nucleotide spans a splice junction associated with intron 1/exon 2 and exon 2/intron 2. In embodiments, the splice junction is selected from a sequence comprising a splice acceptor site or a splice donor site. In embodiments, the splice acceptor site is provided within SEQ ID NO: 2 and the splice donor site is provided within SEQ ID NO: 3. 
     In various embodiments, said dystrophin therapeutic is selected from one or more of a protein or nucleic acid. In embodiments, said nucleic acid is an antisense oligomer. In some embodiments, said antisense oligomer comprising 20 to 50 subunits, and further comprising a targeting sequence complementary to 10 or more contiguous nucleotides in a target region comprising an exon of human dystrophin pre-mRNA; and where, said oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing. 
     Various aspects and embodiments include methods of treating Duchenne muscular dystrophy and related disorders in a subject having a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of dystrophin pre-mRNA. In various embodiments, the method comprises administering to a subject a targeting sequence comprising formula (I) 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, where: 
     each Nu is a nucleobase which taken together form a targeting sequence; 
     Z is an integer from 8 to 48; 
     each Y is independently selected from 0 and —NR 4 , wherein each R 4  is independently selected from H, C 1 -C 6  alkyl, aralkyl, C(═NH)NH 2 , C(O)(CH 2 ) n NR 5 C(═NH)NH 2 , C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 5 C(═NH)NH 2 , and G, wherein R 5  is selected from H and C 1  C 6  alkyl and n is an integer from 1 to 5; 
     T is selected from OH and a moiety of the formula: 
     
       
         
         
             
             
         
       
     
     where: 
     A is selected from —OH, —N(R 7 ) 2 R 8 , where: 
     each R 7  is independently selected from H and C 1 -C 6  alkyl, and 
     R 8  is selected from an electron pair and H, and 
     R 6  is selected from OH, —N(R 9 )CH 2 C(O)NH 2 , and a moiety of the formula: 
     
       
         
         
             
             
         
       
     
     where: 
     R 9  is selected from H and C 1 -C 6  alkyl; and 
     R 19  is selected from G, C(O)—R 11 OH, acyl, trityl, 4 methoxytrityl, C(═NH)NH 2 , C(O)(CH 2 ) m NR 12 C(═NH)NH 2 , and C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 12 C(═NH)NH 2 , where: 
     m is an integer from 1 to 5, 
     R 11  is of the formula —(O-alkyl)y- where y is an integer from 3 to 10 and 
     each of the y alkyl groups is independently selected from C 2 -C 6  alkyl; and 
     R 12  is selected from H and C 1 -C 6  alkyl; 
     each instance of R 1  is independently selected from: 
     —N(R 13 ) 2 R 14 , where each R 13  is independently selected from H and C 1 -C 6  alkyl, and R 14  is selected from an electron pair and H; 
     a moiety of formula (II): 
     
       
         
         
             
             
         
       
     
     where: 
     R 15  is selected from H, G, C 1 -C 6  alkyl, C(═NH)NH 2 , C(O)(CH 2 ) q NR 18 C(═NH)NH 2 , and —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 18 C(═NH)NH 2 , where: 
     R 18  is selected from H and C 1 -C 6  alkyl; and 
     q is an integer from 1 to 5, 
     R 16  is selected from an electron pair and H; and
 
each R 17  is independently selected from H and methyl; and
 
a moiety of formula (III):
 
     
       
         
         
             
             
         
       
     
     where: 
     R 19  is selected from H, C 1 -C 6  alkyl, C(═NH)NH 2 , —C(O)(CH 2 ) r NR 22 C(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 22 C(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 ) 4 NH 2  and G, where: 
     R 22  is selected from H and C 1 -C 6  alkyl; and 
     r is an integer from 1 to 5, 
     R 20  is selected from H and C 1 -C 6  alkyl; and
 
R 21  is selected from an electron pair and H;
 
R 2  is selected from H, G, acyl, trityl, 4-methoxytrityl, C 1 -C 6  alkyl, —C(═NH)NH 2 , —C(O)—R 23 , —C(O)(CH 2 ) s NR 24 C(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 24 C(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , and a moiety of the formula:
 
     
       
         
         
             
             
         
       
     
     where, 
     R 23  is of the formula —(O-alkyl) OH where v is an integer from 3 to 10 and each of the v alkyl groups is independently selected from C 2 -C 6  alkyl; and 
     R 24  is selected from H and C 1 -C 6  alkyl; 
     s is an integer from 1 to 5; 
     L is selected from —C(O)(CH 2 ) 6 C(O)— and —C(O)(CH 2 ) 2 S 2 (CH 2 ) 2 C(O)—; and 
     each R 25  is of the formula —(CH 2 ) 2 OC(O)N(R 26 ) 2  where each R 26  is of the formula —(CH 2 ) 6 NHC(═NH)NH 2 ; and
 
R 3  is selected from an electron pair, H, and C 1 -C 6  alkyl,
 
     wherein G is a cell penetrating peptide (“CPP”) and linker moiety selected from —C(O)(CH 2 ) 5 NH—CPP, —C(O)(CH 2 ) 2 NH—CPP, —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NH—CPP, and —C(O)CH 2 NH—CPP, or G is of the formula: 
     
       
         
         
             
             
         
       
     
     where the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus, with the proviso that up to one instance of G is present, and 
     where the targeting sequence is complementary to 10 or more contiguous nucleotides in a target region comprising an exon of human dystrophin pre-mRNA; and 
     where, said subject has been administered a myostatin therapeutic to thereby suppress one or both of myostatin activity or expression in the subject. 
     In various embodiments, each Nu is independently adenine, guanine, thymine, uracil, cytosine, inosine, hypoxanthine, 2,6-diaminopurine, 5-methyl cytosine, C5-propynyl-modified pyrimidines, or 10-(9-(aminoethoxy)phenoxazinyl). 
     In various embodiments, the target region is selected from (i) a nucleotide sequence wherein at least one nucleotide spans a splice junction associated with said exon; or (ii) a nucleotide sequence wherein no nucleotide spans a splice junction associated with said exon junction. In embodiments, the targeting sequence comprises a sequence selected from SEQ ID NOS: 76-3485, is a fragment of at least 10 contiguous nucleotides of a targeting sequence selected from SEQ ID NOS: 76-3485, or is a variant having at least 90% sequence identity to a targeting sequence selected from SEQ ID NOS: 76-3485. 
     In various embodiments,
         i) Y is O, R 2  is selected from H or G, R 3  is selected from an electron pair or H;   ii) R 2  is G wherein the CPP is of a sequence selected from SEQ ID NOS: 3486-3501;   iii) each R 1  is —N(CH 3 ) 2 ;   iv) at least one R 1  is selected from:       

     
       
         
         
             
             
         
       
     
     or
         v) 50-90% of the R 1  groups are —N(CH 3 ) 2 .       

     In various embodiments, T is of the formula: 
     
       
         
         
             
             
         
       
     
     where A is —N(CH 3 ) 2 , and R 6  is of the formula: 
     
       
         
         
             
             
         
       
         
         
           
             where R 10  is —C(O)R 11 OH. 
           
         
       
    
     In various embodiments, each Y is O, and T is selected from: 
     
       
         
         
             
             
         
       
     
     In various embodiments, T is of the formula: 
     
       
         
         
             
             
         
       
     
     Various aspects include methods of treating Duchenne muscular dystrophy and related disorders in a subject having a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of dystrophin pre-mRNA. In various embodiments, the method comprises administering to a subject a compound comprising formula (VI): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, where:
         each Nu is a nucleobase which taken together form a targeting sequence;   Z is an integer from 8 to 48;   each Y is independently selected from 0 and —NR 4 , where each R 4  is independently selected from H, C 1 -C 6  alkyl,       

     aralkyl, —C(═NH)NH 2 , —C(O)(CH 2 ) n NR 5 C(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 5 C(═NH)NH 2 , and G, where R 5  is selected from H and C 1 -C 6  alkyl and n is an integer from 1 to 5; 
     T is selected from OH and a moiety of the formula: 
     
       
         
         
             
             
         
       
         
         
           
             where: 
             A is selected from —OH and —N(R 7 ) 2 R 8 , where:
           each R 7  is independently selected from H and C 1 -C 6  alkyl, and   R 8  is selected from an electron pair and H, and   
         
             R 6  is selected from OH, —N(R 9 )CH 2 C(O)NH 2 , and a moiety of the formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             where:
           R 9  is selected from H and C 1 -C 6  alkyl; and   R 10  is selected from G, —C(O)—R 11 OH, acyl, trityl, 4-methoxytrityl, —C(═NH)NH 2 , —C(O)(CH 2 ) m NR 12 C(═NH)NH 2 , and —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 12 C(═NH)NH 2 , where:
               m is an integer from 1 to 5,   R 11  is of the formula —(O-alkyl) y - where y is an integer from 3 to 10 and
                   each of the y alkyl groups is independently selected from C 2 -C 6  alkyl; and   
                   
               
         
           
         
       
    
     R 12  is selected from H and C 1 -C 6  alkyl; 
     R 2  is selected from H, G, acyl, trityl, 4-methoxytrityl, C 1 -C 6  alkyl, —C(═NH)NH 2 , and —C(O)—R 23 ; and
         R 3  is selected from an electron pair, H, and C 1 -C 6  alkyl, and wherein the targeting sequence comprises a sequence selected from SEQ ID NOS: 76-3485, is selected from SEQ ID NOS: 76-3485, is a fragment of at least 10 contiguous nucleotides of a sequence selected from SEQ ID NOS: 76-3485, or is a variant having at least 90% sequence identity to a sequence selected from SEQ ID NOS: 76-3485.       

     Various aspects include methods of treating Duchenne muscular dystrophy and related disorders in a subject having a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of human myostatin pre-mRNA. In embodiments, the method comprises administering to a subject a compound comprising formula (I): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, where: 
     each Nu is a nucleobase which taken together form a targeting sequence; 
     Z is an integer from 8 to 48; 
     each Y is independently selected from 0 and —NR4, where each R4 is independently selected from H, C1-C6 alkyl, aralkyl, C(═NH)NH2, C(O)(CH2)nNR5C(═NH)NH2, C(O)(CH2)2NHC(O)(CH2)5NR5C(═NH)NH2, and G, wherein R5 is selected from H and Cl C6 alkyl and n is an integer from 1 to 5; 
     T is selected from OH and a moiety of the formula: 
     
       
         
         
             
             
         
       
     
     where: 
     A is selected from —OH, —N(R 7 ) 2 R 8 , where: 
     each R 7  is independently selected from H and C 1 -C 6  alkyl, and 
     R 8  is selected from an electron pair and H, and 
     R 6  is selected from OH, —N(R 9 )CH 2 C(O)NH 2 , and a moiety of the formula: 
     
       
         
         
             
             
         
       
     
     where: 
     R 9  is selected from H and C 1 -C 6  alkyl; and 
     R 19  is selected from G, C(O)—R 11 OH, acyl, trityl, 4 methoxytrityl, C(═NH)NH 2 , C(O)(CH 2 ) m NR 12 C(═NH)NH 2 , and C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 12 C(═NH)NH 2 , wherein: 
     m is an integer from 1 to 5, 
     R 11  is of the formula —(O-alkyl)y- where y is an integer from 3 to 10 and 
     each of the y alkyl groups is independently selected from C 2 -C 6  alkyl; and 
     R 12  is selected from H and C 1 -C 6  alkyl; 
     each instance of R 1  is independently selected from: 
     —N(R 13 ) 2 R 14 , where each R 13  is independently selected from H and C 1 -C 6  alkyl, and R 14  is selected from an electron pair and H; 
     a moiety of formula (II): 
     
       
         
         
             
             
         
       
     
     where: 
     R 15  is selected from H, G, C 1 -C 6  alkyl, C(═NH)NH 2 , C(O)(CH 2 ) q NR 18 C(═NH)NH 2 , and —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 18 C(═NH)NH 2 , wherein: 
     R 18  is selected from H and C 1 -C 6  alkyl; and 
     q is an integer from 1 to 5, 
     R 16  is selected from an electron pair and H; and
 
each R 17  is independently selected from H and methyl; and
 
a moiety of formula (III):
 
     
       
         
         
             
             
         
       
     
     where: 
     R 19  is selected from H, C 1 -C 6  alkyl, C(═NH)NH 2 , —C(O)(CH 2 ) r NR 22 C(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 22 C(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 ) 4 NH 2  and G, where: 
     R 22  is selected from H and C 1 -C 6  alkyl; and 
     r is an integer from 1 to 5, 
     R 20  is selected from H and C 1 -C 6  alkyl; and
 
R 21  is selected from an electron pair and H;
 
R 2  is selected from H, G, acyl, trityl, 4-methoxytrityl, C 1 -C 6  alkyl, —C(═NH)NH 2 , —C(O)—R 23 , —C(O)(CH 2 ) s NR 24 C(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 24 C(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , and a moiety of the formula:
 
     
       
         
         
             
             
         
       
     
     where, 
     R 23  is of the formula —(O-alkyl) OH wherein v is an integer from 3 to 10 and each of the v alkyl groups is independently selected from C 2 -C 6  alkyl; and 
     R 24  is selected from H and C 1 -C 6  alkyl; 
     s is an integer from 1 to 5; 
     L is selected from —C(O)(CH 2 ) 6 C(O)— and —C(O)(CH 2 ) 2 S 2 (CH 2 ) 2 C(O)—; and 
     each R 25  is of the formula —(CH 2 ) 2 OC(O)N(R 26 ) 2  where each R 26  is of the formula —(CH 2 ) 6 NHC(═NH)NH 2 ; and
 
R 3  is selected from an electron pair, H, and C 1 -C 6  alkyl,
 
     where G is a cell penetrating peptide (“CPP”) and linker moiety selected from —C(O)(CH 2 ) 5 NH—CPP, —C(O)(CH 2 ) 2 NH—CPP, —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NH—CPP, 
     and —C(O)CH 2 NH—CPP, or G is of the formula: 
     
       
         
         
             
             
         
       
     
     where the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus, with the proviso that up to one instance of G is present, and 
     where the targeting sequence is complementary to 10 or more contiguous nucleotides in a target region comprising an exon of human dystrophin pre-mRNA; and 
     where, said subject has been administered a myostatin therapeutic to thereby suppress 
     one or both of myostatin activity or expression in the subject. 
     In various embodiments, each Nu is independently adenine, guanine, thymine, uracil, cytosine, inosine, hypoxanthine, 2,6-diaminopurine, 5-methyl cytosine, C5-propynyl-modified pyrimidines, or 10-(9-(aminoethoxy)phenoxazinyl). 
     In various embodiments, the targeting sequence comprises a sequence selected from SEQ ID NOS: 16-75, is a fragment of at least 10 contiguous nucleotides of a targeting sequence selected from SEQ ID NOS: 16-75, or is a variant having at least 90% sequence identity to a targeting sequence selected from SEQ ID NOS: 16-75. 
     In various embodiments,
         i) Y is O, R 2  is selected from H or G, R 3  is selected from an electron pair or H;   ii) R 2  is G where the CPP is of a sequence selected from SEQ ID NOS: 3486-3501;   iii) each R 1  is —N(CH 3 ) 2 ;   iv) at least one R 1  is selected from:       

     
       
         
         
             
             
         
       
     
     or
         v) 50-90% of the R 1  groups are —N(CH 3 ) 2 .       

     In various embodiments, T is of the formula: 
     
       
         
         
             
             
         
       
     
     where A is —N(CH 3 ) 2 , and R 6  is of the formula: 
     
       
         
         
             
             
         
       
         
         
           
             where R 10  is —C(O)R 11 OH. 
           
         
       
    
     In various embodiments, each Y is O, and T is selected from: 
     
       
         
         
             
             
         
       
     
     In various embodiments, T is of the formula: 
     
       
         
         
             
             
         
       
     
     Various aspects include, methods of treating Duchenne muscular dystrophy and related disorders in a subject having a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of myostatin pre-mRNA. In various embodiments, the method comprises administering to a subject a compound comprising formula (VI): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, where:
         each Nu is a nucleobase which taken together form a targeting sequence;   Z is an integer from 8 to 48;   each Y is independently selected from O and —NR 4 , wherein each R 4  is independently selected from H, C 1 -C 6  alkyl,       

     aralkyl, —C(═NH)NH 2 , —C(O)(CH 2 )—NR 5 C(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 5 C(═NH)NH 2 , and G, where R 5  is selected from H and C 1 -C 6  alkyl and n is an integer from 1 to 5;
         T is selected from OH and a moiety of the formula:       

     
       
         
         
             
             
         
       
         
         
           
             where: 
             A is selected from —OH and —N(R 7 ) 2 R 8 , where:
           each R 7  is independently selected from H and C 1 -C 6  alkyl, and   R 8  is selected from an electron pair and H, and   
         
             R 6  is selected from OH, —N(R 9 )CH 2 C(O)NH 2 , and a moiety of the formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             where:
           R 9  is selected from H and C 1 -C 6  alkyl; and   R 10  is selected from G, —C(O)—R 11 OH, acyl, trityl, 4-methoxytrityl, —C(═NH)NH 2 , —C(O)(CH 2 ) m NR 12 C(═NH)NH 2 , and —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 12 C(═NH)NH 2 , where:
               m is an integer from 1 to 5,   R 11  is of the formula —(O-alkyl) y - where y is an integer from 3 to 10 and
                   each of the y alkyl groups is independently selected from C 2 -C 6  alkyl; and   
                   
               
         
           
         
       
    
     R 12  is selected from H and C 1 -C 6  alkyl; 
     R 2  is selected from H, G, acyl, trityl, 4-methoxytrityl, C 1 -C 6  alkyl, —C(═NH)NH 2 , and —C(O)—R 23 ; and
         R 3  is selected from an electron pair, H, and C 1 -C 6  alkyl, and where the targeting sequence comprises a sequence selected from SEQ ID NOS: 16-75, is selected from SEQ ID NOS: 16-75, is a fragment of at least 10 contiguous nucleotides of a sequence selected from SEQ ID NOS: 16-75, or is a variant having at least 90% sequence identity to a sequence selected from SEQ ID NOS: 16-75.       

     Various aspects include a dystrophin-related pharmaceutical composition, comprising an antisense oligomer compound of 20 to 50 subunits and a pharmaceutically acceptable carrier, the compound comprising: at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and a targeting sequence complementary to 10 or more contiguous nucleotides in a target region comprising an exon of human dystrophin pre-mRNA; 
     together with a myostatin-related pharmaceutical composition, comprising an antisense oligomer compound of 12 to 40 subunits and a pharmaceutically acceptable carrier, the compound comprising: at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and 
     a targeting sequence complementary to 12 or more contiguous nucleotides in a target region comprising an exon of human myostatin pre-mRNA. In various embodiments, the dystrophin-related composition and the myostatin-related composition are provided in the same pharmaceutical composition. 
     Various aspects include, methods for modulating myostatin expression in a subject having a genetic mutation amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of human myostatin pre-mRNA, the method comprising: administering to the subject an effective amount of an antisense oligomer comprising 12 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre-mRNA; and where, said oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; binding the antisense oligomer to the target region in the myostatin pre-mRNA transcript; and, inhibiting transcription of the target region into a human myostatin mRNA transcript, where said subject has been administered a dystrophin therapeutic that increases dystrophin expression in the subject. 
     Various aspects include, methods for decreasing expression of exon 2 in a subject having a genetic mutation amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of human myostatin pre-mRNA, the method comprising: administering to the subject an effective amount of an antisense oligomer comprising 12 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre-mRNA and inhibiting transcription of exon 2 in a myostatin mRNA transcript, where said subject has been administered a dystrophin therapeutic that increases dystrophin expression in the subject. In various embodiments, exon 2 expression is decreased by about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% in a myostatin mRNA transcript. 
     Various aspects include, methods for decreasing the accumulation of functional myostatin protein in a muscle cell or tissue in a subject having a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of human myostatin pre-mRNA, the method comprising: administering to the subject an effective amount of an antisense oligomer comprising 12 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre-mRNA, and inhibiting transcription of exon 2 in a myostatin mRNA transcript, where said subject has been administered a dystrophin therapeutic that increases dystrophin expression in the subject. 
     Various aspects include, a medicament for the treatment of Duchenne muscular dystrophy and related disorders comprising: an antisense oligomer compound comprising 12 to 40 subunits, comprising at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre mRNA; and a dystrophin therapeutic that increases dystrophin expression. 
     Various aspects include, methods for inhibiting the progression of Duchenne muscular dystrophy and related disorders in a subject having a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of human myostatin pre-mRNA, the method comprising: administering to the subject an effective amount of an antisense oligomer comprising 12 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre-mRNA; and, inhibiting transcription of exon 2 in a myostatin mRNA transcript, where said subject has been administered a dystrophin therapeutic that increases dystrophin expression in the subject to thereby inhibit the progression of Duchenne muscular dystrophy. 
     Various aspects include, methods of decreasing the accumulation of a functional myostatin protein in a subject with Duchenne muscular dystrophy and related disorders, said method comprising: administering to the subject an effective amount of an antisense oligomer comprising 12 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre-mRNA; inhibiting transcription of exon 2 in a myostatin mRNA transcript, where the accumulation of functional myostatin protein in the subject is decreased, and where said subject has been administered a dystrophin therapeutic that increases dystrophin expression in the subject. 
     Various aspects include, methods for treating Duchenne muscular dystrophy and related disorders in a subject in need of such treatment, comprising: administering an antisense oligomer in an effective amount to result in a peak blood concentration of at least about 200-400 nM of antisense oligomer in the subject. 
     Various aspects include, a method of treating skeletal muscle mass deficiency in a subject having a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of human myostatin pre-mRNA, the method comprising: (a) measuring blood or tissue levels of myostatin protein in the subject; (b) administering to the subject, an effective amount of an antisense oligomer comprising 12 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre-mRNA; (c) inhibiting transcription of exon 2 in a myostatin mRNA transcript; (d) measuring myostatin protein levels in the subject after a select time; and, (e) repeating said administering using the levels measured in (d) to adjust the dose or dosing schedule of the amount of antisense oligomer administered, wherein the level of myostatin protein is decreased in the subject after administering the antisense oligomer, and where said subject has been administered a dystrophin therapeutic that increases dystrophin expression in the subject. 
     Various aspects include, methods of inhibiting the progression of Duchenne muscular dystrophy and related disorders in a subject having a mutation in the dystrophin gene that is amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of dystrophin pre-mRNA, the method comprising: administering to the subject an effective amount of an antisense oligomer comprising 17 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides in a target region comprising an exon of human dystrophin pre-mRNA, wherein the antisense oligomer induces skipping of the exon; where, said oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and where, said subject has been administered a myostatin therapeutic that inhibits one or both of myostatin activity and expression in the subject to thereby inhibit the progression of Duchenne muscular dystrophy. 
     Various aspects include, methods of inhibiting the progression of Duchenne muscular dystrophy, the method comprising: administering to the subject an effective amount of an antisense oligomer comprising 12 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre-mRNA; and where, said oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and where said subject has been administered a dystrophin therapeutic that increases dystrophin expression in the subject to thereby inhibit the progression of Duchenne muscular dystrophy. 
     Various aspects and embodiments include antisense oligomers further comprising an arginine-rich peptide sequence conjugated to the 3′ terminal end or the 5′ terminal end of the antisense oligomer, where the arginine-rich peptide sequence comprises a sequence selected from SEQ ID NOS: 3486-3501. 
     Various aspects include, a composition comprising: an antisense oligomer comprising 17 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides in a target region comprising an exon of human dystrophin pre-mRNA; where said dystrophin-targeted oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and an antisense oligomer comprising 12 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human myostatin pre-mRNA; where said myostatin-targeted oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified intemucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing. 
     Various aspects and embodiments include administering a dystrophin therapeutic agent and a myostatin therapeutic agent to a subject where said subject is a pediatric patient of age 7 or greater. 
     Various aspects include methods for modulating dystrophin expression in a subject having a genetic mutation amenable to treatment by an antisense oligomer capable of inducing exon skipping during processing of human myostatin pre-mRNA, the methodcomprising: administering to the subject an effective amount of an antisense oligomer comprising 17 to 40 subunits, and further comprising a targeting sequence complementary to 12 or more contiguous nucleotides comprising an exon of human dystrophin pre-mRNA; and where, said oligomer comprises at least one subunit that is a nucleotide analog having (i) a modified intemucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; wherein said subject has been administered a myostatin therapeutic that inhibits one or both of myostatin activity and myostatin expression in the subject. 
     Various aspects and embodiments further include methods of modulating muscle mass in subjects with DMD and related disorders are provided. 
     In another aspect, the disclosure provides a method for treating a patient with DMD, the method comprising administering to the subject one or both of any dystrophin therapeutic described herein and any myostatin therapeutic described herein to thereby treat DMD. The patient can be one having a mutation in the DMD gene that is amenable to exon skipping, e.g., using an oligonucleotide capable of inducing exon skipping. In some embodiments, the patient has a mutation in the DMD gene that is amenable to exon 51 skipping. In some embodiments, the patient has a mutation in the DMD gene that is amenable to exon 53 skipping. In some embodiments, the patient has a mutation in the DMD gene that is amenable to exon 45 skipping. In some embodiments, the patient has a mutation in the DMD gene that is amenable to exon 44 skipping. In some embodiments, the patient has a mutation in the DMD gene that is amenable to exon 52 skipping. In some embodiments, the patient has a mutation in the DMD gene that is amenable to exon 50 skipping. In some embodiments, the patient has a mutation in the DMD gene that is amenable to exon 8 skipping. In some embodiments, the patient has a mutation in the DMD gene that is amenable to exon 55 skipping. 
     In another aspect, the disclosure provides a composition (e.g., a pharmaceutical composition) comprising any one or more of the dystrophin therapeutics described herein and one or more of the myostatin therapeutics described herein. 
     In some embodiments of the methods or compositions described herein, the dystrophin therapeutic is eteplirsen. 
     In some embodiments of the methods or compositions described herein, the dystrophin therapeutic does not comprise, and does not consist of, the sequence set forth in SEQ ID NO: 927. 
     In some embodiments of the methods or compositions described herein, dystrophin is human dystrophin. In some embodiments of the methods or compositions described herein, myostatin is human myostatin. In some embodiments of the methods or compositions described herein, the subject is human. 
     In some embodiments of any of the methods or compositions described herein, the subject is a human (e.g., a human patient). In some embodiments of any of the methods or compositions described herein, the subject is a male subject. In some embodiments of any of the methods or compositions described herein, the subject is a pediatric patient. In some embodiments of any of the methods or compositions described herein, the patient is seven years of age or older. In some embodiments of any of the methods or compositions described herein, the patient is at least seven years of age, but less than about 21 years of age. 
     In some embodiments of any of the methods or compositions described herein, one or both of the dystrophin therapeutic and the myostatin therapeutic are systemically delivered to the subject, e.g., by intravenous administration. In some embodiments of any of the methods or compositions described herein, the dystrophin therapeutic is systemically delivered to the subject. In some embodiments of any of the methods or compositions described herein, the myostatin therapeutic is systemically delivered to the subject. 
     In some embodiments of any of the methods or compositions described herein, one or both of the dystrophin therapeutic and the myostatin therapeutic are chronically administered to the subject. For example, in some embodiments of any of the methods or compositions described herein, one or both of the therapeutic agents can each, independently, be administered daily, weekly, monthly, bi weekly, or bi monthly. In some embodiments of any of the methods or compositions described herein, a therapeutically effective amount of one or both of the therapeutic agents can each, independently, can be delivered to the subject as a single dose (e.g., a single weekly dose) or as multiple doses (e.g., two or more, e.g., three, four, five, six, or seven doses) within a treatment period, e.g., once per week (weekly) or twice per week. 
     In some embodiments of any of the methods described herein, the dystrophin therapeutic is administered first in time and the myostatin therapeutic is administered second in time. For example, a dystrophin therapeutic (e.g., eteplirsen) can be administered first in time in an amount for a duration sufficient to increase dystrophin production in muscle cells of the subject, prior to administering the myostatin therapeuitic to the subject. Thus, in some embodiments, a dystrophin therapeutic (e.g., eteplirsen) is administered to a subject at about 30 mg per kg body weight of the subject once weekly for a period of time (e.g., 6 months, 1 year, 18 months, 2 years or more) to increase dystrophin expression in the muscle cells of the subject, prior to administering the myostatin therapeutic. In some embodiments, a dystrophin therapeutic (e.g., eteplirsen) is administered to a subject at about 30 to about 50 mg per kg body weight of the subject once weekly for a period of time (e.g., 6 months, 1 year, 18 months, 2 years or more) to increase dystrophin expression in the muscle cells of the subject, prior to administering the myostatin therapeutic. In some embodiments of any of the methods described herein, the myostatin therapeutic is administered first in time and the dystrophin therapeutic is administered second in time. 
     In some embodiments, the antisense oligonucleotide compounds for use in the compositions and methods described herein do not include a cell-penetrating peptide. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1A  illustrates a modified oligomer at the 5′ end to add a linker.  FIGS. 1B and 1C  illustrates an antisense oligonucleotide conjugated to a cell penetrating peptide (CPP).  FIGS. 1D, 1E, 1F and 1G  illustrate a repeating subunit segment of exemplary morpholino oligonucleotides. 
         FIG. 2A  illustrates preparation of trityl piperazine phenyl carbamate.  FIG. 2B  illustrates preparation of a resin/reagent mixture. 
         FIG. 3A  illustrates a gel electrophoresis of RT-PCR products of myostatin exon 2 skipping in human Rhabdomyosarcoma (RD) cells.  FIG. 3B  illustrates skipping efficiency of myostatin exon 2 in RD cells (%). 
         FIG. 4A  illustrates a gel electrophoresis of RT-PCR products of myostatin exon 2 skipping in RD cells.  FIG. 4B  illustrates relative densitometric analysis of myostatin exon 2 skipping. 
         FIG. 5A  illustrates myostatin exon 2 skipping in C2C12 and H2Kb mdx  cells.  FIG. 5B  illustrates densitometric analysis of RT-PCR products myostatin exon 2 skipping efficiency in C2C12 cells (%).  FIG. 5C  illustrates densitometric analysis of RT-PCR products myostatin exon 2 skipping efficiency in H2Kb mdx  cells (%). 
         FIG. 6A  illustrates gel electrophoresis products of myostatin exon 2 skipping in tibialis anterior (TA) muscle.  FIG. 6B  illustrates muscle mass normalized to body weight.  FIG. 6C  illustrates densitometric analysis of RT-PCR products of myostatin exon 2 skipping. 
         FIG. 7A  illustrates a gel electrophoresis of myostatin exon 2 skipping in mdx mice muscles.  FIG. 7B  illustrates densitometric analysis of RT-PCR products of myostatin exon 2 skipping in mdx mice.  FIG. 7C  illustrates muscle weight normalized to initial body weight in mdx mice.  FIG. 7D  illustrates muscle weight normalized to final body weight in mdx mice. 
         FIG. 8A  illustrates increase in body weight in mdx mice administered 10 mg/kg BPMO.  FIG. 8B  illustrates increase in muscle mass in mdx mice administered 10 mg/kg BPMO.  FIG. 8C  illustrates increase in body weight in mdx mice administered 20 mg/kg BPMO. 
         FIG. 8D  illustrates increase in muscle mass in mdx mice administered 20 mg/kg BPMO. 
         FIG. 9A  illustrates grip strength test of mdx mice administered 10 mg/kg BPMO. 
         FIG. 9B  illustrates grip strength test of mdx mice administered 20 mg/kg BPMO.  FIG. 9C  illustrates electrophysiology test in TA muscles in mdx mice administered 10 mg/kg BPMO. 
         FIG. 10A  illustrates gel electrophoresis of RT-PCR products of myostatin exon 2 skipping in the diaphragm (DIA).  FIG. 10B  illustrates densitometric analysis of RT-PCR products of myostatin exon 2 skipping in the DIA.  FIG. 10C  illustrates gel electrophoresis of RT-PCR products of myostatin exon 2 skipping in the TA.  FIG. 10D  illustrates densitometric analysis of RT-PCR products of myostatin exon 2 skipping in the TA. 
         FIG. 11A  illustrates body weight normalized to initial weight of young dystrophic miceC57BL10 administered saline (positive control), mdx mice administered saline (negative control), mdx mice administered BPMO-M23D (10 mg/kg), mdx mice administered BPMO-M23D (10 mg/kg) &amp; BPMO-MSTN (10 mg/kg), or mdx mice administered BPMO-MSTN (10 mg/kg). Statistical analysis was by one-way ANOVA &amp; Bonferroni post-hoc test comparing all groups at each week; error bars represent the S.E.M.  FIG. 11B  illustrates grip strength analysis of mouse forelimbs force in young dystrophic mice C57BL10 administered saline (positive control), mdx mice administered saline (negative control), mdx mice administered BPMO-M23D (10 mg/kg), mdx mice administered BPMO-M23D (10 mg/kg) &amp; BPMO-MSTN (10 mg/kg), or mdx mice administered BPMO-MSTN (10 mg/kg). 
         FIG. 12A  illustrates quantification of dystrophin RNA reframing by exon skipping. 
         FIG. 12B  illustrates quantification of dystrophin protein expression by immunoblot.  FIG. 12C  illustrates quantification of myostatin exon 2 skipping. 
         FIG. 13A  illustrates variance coefficient of the minimal Feret&#39;s diameter in the TA of young dystrophin mice.  FIG. 13B  illustrates percentage of centrally nucleated fibers in TA muscles of young dystrophin mice. 
         FIG. 14A  illustrates increase in body weight in mdx mice.  FIG. 14B  illustrates increase in muscle mass in mdx mice administered BPMO-M23D or BPMO-M23D+BPMO-MSTN.  FIG. 14C  illustrates grip strength analysis of forelimb force in mdx mice administered BPMO-M23D or BPMO-M23D+BPMO-MSTN.  FIG. 14D  illustrates electrophysiology measurements in situ of mdx mice administered BPMO-M23D or BPMO-M23D+BPMO-MSTN. 
         FIG. 15A  illustrates a gel electrophoresis showing dystrophin RNA reframing by exon skipping in muscles of mdx mice administered BPMO-M23D or BPMO-M23D+BPMO-MSTN.  FIG. 15B  illustrates relative densitometric analysis of RT-PCR products in mdx mice administered BPMO-M23D or BPMO-M23D+BPMO-MSTN. 
         FIG. 16A  illustrates dystrophin protein expression in muscles harvested from mdx mice administered BPMO-M23D or BPMO-M23D+BPMO-MSTN.  FIG. 16B  illustrates relative densitometric quantification of dystrophin protein expression in muscles harvested from mdx mice administered BPMO-M23D or BPMO-M23D+BPMO-MSTN. 
         FIG. 17A  illustrates a gel electrophoresis showing variable myostatin skipping in muscles of mdx mice administered BPMO-M23D or BPMO-M23D+BPMO-MSTN.  FIG. 17B  illustrates relative densitometric analysis of RT-PCR products of myostatin skipping in mdx mice administered BPMO-M23D or BPMO-M23D+BPMO-MSTN. 
         FIG. 18A  illustrates gripstrength testing in mice 15 reads per mouse.  FIG. 18B  illustrates gripstength testing in mice 3 averages of 15 reads per mouse.  FIG. 18C  illustrates gripstrength testing in mice 3 highest reads per mouse. 
     
    
    
     DETAILED DESCRIPTION 
     The following description is merely exemplary in nature and is not intended to limit the present invention, its applications, or its uses. It should be understood that throughout the drawings, corresponding reference numerals indicate like or corresponding parts and features. The description of specific examples indicated in various embodiments of the present invention are intended for purposes of illustration only and are not intended to limit the scope of the invention disclosed herein. Moreover, recitation of multiple embodiments having stated features is not intended to exclude other embodiments having additional features or other embodiments incorporating different combinations of the stated features. 
     Furthermore, the detailed description of various embodiments herein makes reference to the accompanying drawing FIGS, which show various embodiments by way of illustration. While the embodiments are described in sufficient detail to enable those skilled in the art to practice the invention, it should be understood that other embodiments may be realized and that logical and mechanical changes may be made without departing from the spirit and scope of the present invention. Thus, the detailed description herein is presented for purposes of illustration only and not of limitation. For example, steps or functions recited in descriptions, any method, system, or process, may be executed in any order and are not limited to the order presented. Moreover, any of the step or functions thereof may be outsourced to or performed by one or more third parties. Furthermore, any reference to singular includes plural embodiments, and any reference to more than one component may include a singular embodiment. 
     I. DEFINITIONS 
     Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the subject matter of the present disclosure, preferred methods and materials are described. For the purposes of the present disclosure, the following terms are defined below. 
     The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. 
     The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term “about” is intended to modify a numerical value above and below the stated value by a variance of 10%. 
     Throughout this disclosure, unless the context requires otherwise, the words “comprise,” “comprises,” and “comprising” will be understood to imply the inclusion of a stated step or element or group of steps or elements but not the exclusion of any other step or element or group of steps or elements. 
     The term “consisting of” means including, and limited to, whatever follows the phrase “consisting of” Thus, the phrase “consisting of” indicates that the listed elements are required or mandatory, and that no other elements may be present. The term “consisting essentially of” means including any elements listed after the phrase, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure for the listed elements. Thus, the phrase “consisting essentially of” indicates that the listed elements are required or mandatory, but that other elements are optional and may or may not be present depending upon whether or not they materially affect the activity or action of the listed elements. 
     The terms “administering,” or “administer” include delivery of the therapeutic agent including modified antisense oligomers of the disclosure to a subject either by local or systemic administration. 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. 
     “Co-administration” or “co-administering” or “combination therapy” as used herein, generally refers to the administration of a DMD exon-skipping antisense oligonucleotide in combination with one or more myostatin therapeutic compounds disclosed herein. In other words, the terms “co-administering” or “co-administration” or “combination therapy” mean the administration of the DMD exon-skipping antisense oligonucleotide, such as eteplirsen, concomitantly in a pharmaceutically acceptable dosage form with one or more myostatin therapeutic compounds and optionally one or more glucocorticoids disclosed herein: (i) in the same dosage form, e.g., the same tablet or pharmaceutical composition, meaning a pharmaceutical composition comprising a DMD exon-skipping antisense oligonucleotide, such as eteplirsen, one or more myostatin therapeutic compounds disclosed herein, and optionally one or more glucocorticoids and a pharmaceutically acceptable carrier; (ii) in a separate dosage form having the same mode of administration, e.g., a kit comprising a first pharmaceutical composition suitable for parenteral administration comprising a DMD exon-skipping antisense oligonucleotide, such as eteplirsen and a pharmaceutically acceptable carrier, a second pharmaceutical composition suitable for parenteral administration comprising one or more myostatin therapeutic compounds disclosed herein and a pharmaceutically acceptable carrier, and optionally a third pharmaceutical composition suitable for parenteral administration comprising one or more glucocorticoids disclosed herein and a pharmaceutically acceptable carrier; and (iii) in a separate dosage form having different modes of administration, e.g., a kit comprising a first pharmaceutical composition suitable for parenteral administration comprising a DMD exon-skipping antisense oligonucleotide, such as eteplirsen and a pharmaceutically acceptable carrier, a second pharmaceutical composition suitable for oral administration comprising one or more myostatin therapeutic compounds disclosed herein and a pharmaceutically acceptable carrier, and optionally a third pharmaceutical composition suitable for oral administration comprising one or more glucocorticoids disclosed herein and a pharmaceutically acceptable carrier. 
     Further, those of skill in the art given the benefit of the present disclosure will appreciate that when more than one myostatin therapeutic compound disclosed herein is being administered, the agents need not share the same mode of administration, e.g., a kit comprising a first pharmaceutical composition suitable for parenteral administration comprising a DMD exon-skipping antisense oligonucleotide, such as eteplirsen and a pharmaceutically acceptable carrier, a second pharmaceutical composition suitable for oral administration comprising a first myostatin therapeutic compound disclosed herein and a pharmaceutically acceptable carrier, and a third pharmaceutical composition suitable for parenteral administration comprising a second non-steroidal anti-inflammatory compound disclosed herein and a pharmaceutically acceptable carrier. Those of skill in the art will appreciate that the concomitant administration referred to above in the context of “co-administering” or “co-administration” means that the pharmaceutical composition comprising the DMD exon-skipping antisense oligonucleotide and a pharmaceutical composition(s) comprising the myostatin therapeutic compound can be administered on the same schedule, i.e., at the same time and day, or on a different schedule, i.e., on different, although not necessarily distinct, schedules. 
     In that regard, when the pharmaceutical composition comprising a DMD exon-skipping antisense oligonucleotide and a pharmaceutical composition(s) comprising the myostatin therapeutic compound is administered on a different schedule, such a different schedule may also be referred to herein as “background” or “background administration.” For example, the pharmaceutical composition comprising a DMD exon-skipping antisense oligonucleotide may be administered in a certain dosage form twice a day, and the pharmaceutical composition(s) comprising the myostatin therapeutic compound may be administered once a day, such that the pharmaceutical composition comprising the DMD exon-skipping antisense oligonucleotide may but not necessarily be administered at the same time as the pharmaceutical composition(s) comprising the myostatin therapeutic compound during one of the daily administrations. Of course, other suitable variations to “co-administering”, “co-administration” or “combination therapy” will be readily apparent to those of skill in the art given the benefit of the present disclosure and are part of the meaning of this term. 
     “Chronic administration,” as used herein, refers to continuous, regular, long-term therapeutic administration, i.e., periodic administration without substantial interruption. For example, daily, for a period of time of at least several weeks or months or years, for the purpose of treating muscular dystrophy in a patient. For example, weekly, for a period of time of at least several months or years, for the purpose of treating muscular dystrophy in a patient (e.g., weekly for at least six weeks, weekly for at least 12 weeks, weekly for at least 24 weeks, weekly for at least 48 weeks, weekly for at least 72 weeks, weekly for at least 96 weeks, weekly for at least 120 weeks, weekly for at least 144 weeks, weekly for at least 168 weeks, weekly for at least 180 weeks, weekly for at least 192 weeks, weekly for at least 216 weeks, or weekly for at least 240 weeks). In certain embodiments, the DMD exon skipping compound, such as eteplirsen, is chronically administered 30 mg/kg once weekly via an intravenous infusion in combination with a myostatin therapeutic compound disclosed herein. 
     The terms “contacting a cell,” “introducing” or “delivering” include delivery of the therapeutic agents of the disclosure into a cell by methods routine in the art, including, transfection (e.g., liposome, calcium-phosphate, polyethyleneimine), electroporation (e.g., nucleofection), microinjection). 
     The term “alkyl” refers to a linear (i.e., unbranched or acyclic), branched, cyclic, or polycyclic non aromatic hydrocarbon groups, which are optionally substituted with one or more functional groups. Unless otherwise specified, “alkyl” groups contain one to eight, and preferably one to six carbon atoms. C 1 -C 6  alkyl, is intended to include at least C 1 , C 2 , C 3 , C 4 , C 5 , and C 6  alkyl groups. Lower alkyl refers to alkyl groups containing 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, isopentyl tert-pentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, etc. Alkyl may be substituted or unsubstituted. Illustrative substituted alkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl, substituted phenethyl, etc. 
     The term “alkoxy” refers to a subset of alkyl in which an alkyl group as defined above with the indicated number of carbons attached through an oxygen bridge. For example, “alkoxy” refers to groups —O-alkyl, where the alkyl group contains 1 to 8 carbons atoms of a linear, branched, cyclic configuration. Examples of “alkoxy” include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, t-butoxy, n-butoxy, s-pentoxy and the like. 
     The term “aryl” used alone or as part of a larger moiety as in “aralkyl,”, “aralkoxy,” or “aryloxy-alkyl,” refers to aromatic ring groups having six to fourteen ring atoms, such as phenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. An “aryl” ring may contain one or more substituents. The term “aryl” may be used interchangeably with the term “aryl ring.” “Aryl” also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Non-limiting examples of useful aryl ring groups include phenyl, hydroxyphenyl, halophenyl, alkoxyphenyl, dialkoxyphenyl, trialkoxyphenyl, alkylenedioxyphenyl, naphthyl, phenanthryl, anthryl, phenanthro and the like, as well as 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring. 
     The term “acyl” refers to a C(O)R group (in which R signifies H, alkyl or aryl as defined above). Examples of acyl groups include formyl, acetyl, benzoyl, phenylacetyl and similar groups. 
     The term “homolog” refers to compounds differing regularly by the successive addition of the same chemical group. For example, a homolog of a compound may differ by the addition of one or more —CH2— groups, amino acid residues, nucleotides, or nucleotide analogs. 
     The terms “cell penetrating peptide” (CPP) or “a peptide moiety which enhances cellular uptake” are used interchangeably and refer to cationic cell penetrating peptides, also called “transport peptides,” “carrier peptides,” or “peptide transduction domains.” For example, a peptide-conjugated phosphoramidate or phosphorodiamidate morpholino (PPMO) may include a cell penetrating peptide or peptide moiety which enhances cellular uptake as described herein. In various embodiments, a peptide may be covalently bonded to the modified antisense oligomer. In further embodiments, a peptide may be conjugated to the 3′ end or the 5′ end of the modified antisense oligomer. In further embodiments, a peptide may be linked to a piperazinyl moiety or to a nitrogen atom of the 3′ terminal morpholino ring. In some embodiments, a cell penetrating peptide or peptide moiety which enhances cellular uptake may include an arginine-rich peptide as described herein. In a non-limiting example, modified antisense oligomers as disclosed herein can be coupled to an arginine-rich peptide such as (Arg) 6 Gly (6 arginine and 1 glycine linked to an oligonucleotide). 
     The peptides, as shown herein, have the capability of inducing cell penetration within about or at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of cells of a given cell culture population and allow macromolecular translocation within multiple tissues in vivo upon systemic administration. In some embodiments, the CPPs are of the formula [(C(O)CHR′NH) m ]R″ where R′ is a side chain of a naturally occurring amino acid or a one- or two-carbon homolog thereof, R″ is selected from Hydrogen or acyl, and m is an integer up to 50. Additional CPPs are well-known in the art and are disclosed, for example, in U.S. Published Application No. 20100016215, which is hereby incorporated by reference in its entirety. In other embodiments, m is an integer selected from 1 to 50 where, when m is 1, the moiety is a single amino acid or derivative thereof. 
     The term “amino acid” refers to a compound comprising a carbon atom to which are attached a primary amino group, a carboxylic acid group, a side chain, and a hydrogen atom. For example, the term “amino acid” includes, but is not limited to, Glycine, Alanine, Valine, Leucine, Isoleucine, Asparagine, Glutamine, Lysine, Aspartic Acid, Histidine, Methionine, Proline, Phenylalanine, Threonine, Tryptophan, Cysteine, Glutamic Acid, Serine, Tyrosine, Pyrolysine, Selenocystenine and Arginine. Additionally, as used herein, “amino acid” also includes derivatives of amino acids such as esters, and amides, and salts, as well as other derivatives, including derivatives having pharmaco properties upon metabolism to an active form. Accordingly, the term “amino acid” is understood to include naturally occurring and non-naturally occurring amino acids. 
     The term “an electron pair” refers to a valence pair of electrons that are not bonded or shared with other atoms. 
     The term “homology” refers to the amount or degree of similarity between two or more amino acid sequences or two or more nucleotide sequences. In some examples, sequence homology may include one or more conservative substitutions such that one or more substitutions would not affect the basic structure or function of a subject protein A conservative nucleotide substitution may include a substitution of one nucleic acid for another such that the substitution does not alter the amino acid encoded by the codon. A conservative amino acid substitution may include a substitution of one amino acid for another such that the substituted amino acid is of the same or similar class as the substituting amino acid, for example substitution of an aliphatic amino acid with another aliphatic amino acid. Homology may be determined using sequence comparison programs such as GAP (Deveraux et al., 1984, Nucleic Acids Research 12, 387-395). In this way sequences of a similar or substantially different length to those cited herein could be compared by insertion of gaps into the alignment, such gaps being determined, for example, by the comparison algorithm used by GAP. 
     The term “isolated” refers to a material that is substantially or essentially free from components that normally accompany it in its native state. For example, an “isolated oligonucleotide,” or “isolated oligomer” as used herein, may refer to an oligomer that has been purified or removed from the sequences that flank it in a naturally-occurring state, e.g., a DNA fragment that is removed from the sequences that are adjacent to the fragment in the genome. The term “isolating” as it relates to cells may refer to the purification of cells (e.g., fibroblasts, lymphoblasts) from a source subject (e.g., a subject with an oligonucleotide repeat disease). In the context of mRNA or protein, “isolating” may refer to the recovery of mRNA or protein from a source, e.g., cells. 
     The term “modulate” includes to “increase” or “decrease” one or more quantifiable parameters, optionally by a defined and/or statistically significant amount. By “increase” or “increasing,” “enhance” or “enhancing,” or “stimulate” or “stimulating,” refers generally to the ability of one or more modified antisense oligomer compounds or compositions, and/or one or more therapeutic agents to produce or cause a greater physiological response (e.g., downstream effects) in a cell or a subject relative to the response caused by either no antisense oligomer compound and/or therapeutic agent, or a control compound. Relevant physiological or cellular responses (in vivo or in vitro) will be apparent to persons skilled in the art, and may include a decrease in the inclusion of exon 2 (or an increase in the exclusion of exon 2) in myostatin mRNA, and/or a decrease in the expression of functional myostatin protein in a cell, or tissue, such as in a subject in need thereof. Other relevant physiological or cellular responses (in vivo or in vitro) may include a decrease in the inclusion of (or an increase in the exclusion of) one or more exons having a genetic mutation in dystrophin mRNA, and/or an increase in the expression of functional or semi-functional dystrophin protein in a cell, or tissue. A “decreased” or “reduced” amount is typically a “statistically significant” amount, and may include a decrease that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 or more times less (e.g., 100, 500, 1000 times), including all integers and decimal points in between and above 1 (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9), in comparison to the amount produced by a subject in need thereof in the absence of administration of a modified antisense oligomer compound and/or therapeutic (e.g. the “native” or “natural” rate of expression of a specific subject or cohort) or a control compound. The terms “reduce” or “inhibit” may relate generally to the ability of one or more antisense oligomer compounds or compositions, and/or one or more therapeutic to “decrease” a relevant physiological or cellular response, such as a symptom of a disease or condition described herein, as measured according to routine techniques in the diagnostic art. An “increased” or “enhanced” amount is typically a “statistically significant” amount, and may include an increase that is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 30, 40, 50 or more times greater than (e.g., 100, 500, 1000 times), including all integers and decimal points in between and above 1 (e.g., 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9), in comparison to the amount produced by a subject in need thereof in the absence of administration of a modified antisense oligomer compound and/or therapeutic (e.g. the “native” or “natural” rate of expression of a specific subject or cohort) or a control compound. The term “enhance” may relate generally to the ability of one or more modified antisense oligomer compounds or compositions, and/or one or more therapeutic to “increase” a relevant physiological or cellular response, such as a symptom of a disease or condition described herein, as measured according to routine techniques in the diagnostic art. 
     Relevant physiological or cellular responses (in vivo or in vitro) will be apparent to persons skilled in the art, and may include reductions in the symptoms or pathology of Duchenne muscular dystrophy (DMD) and related disorders, such as Becker muscular dystrophy (BMD), limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, muscle wasting conditions or disorders, such as AIDS, cancer or chemotherapy related muscle wasting, and fibrosis or fibrosis-related disorders (for example, skeletal muscle fibrosis). In other embodiments, methods of treating Duchenne muscular dystrophy and related disorders are provided, for example, where a reduction in symptoms or pathology may accompany or relate to an increase in the expression of functional dystrophin protein and/or a decrease in the expression of functional myostatin protein. An “increase” in a response may be “statistically significant” as compared to the response produced by a subject in need thereof in the absence of administration of a modified antisense oligomer compound and/or therapeutic (e.g. when compared to the “native” or “natural” rate of expression of a specific subject or cohort) or when compared to a control compound, and may include a 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% increase, including all integers in between. 
     The term “therapeutic” or “therapeutic agent” as used herein means an agent capable of producing a therapeutic effect. In some embodiments, a therapeutic is, or comprises a polypeptide, a polypeptide analog, a nucleic acid, a nucleic acid analog, an aptamer, or a small molecule. “Polypeptide,” “peptide,” and “protein” are used interchangeably and mean any peptide-linked chain of amino acids, regardless of length or post-translational modification. A polypeptide can be wildtype proteins, functional fragments of a wildtype protein, or variants of a wildtype protein or fragment. Variants can comprise one or more amino acid substitutions, deletions, or insertions. The substitutions can be conservative or non-conservative. Conservative substitutions typically include substitutions within the following groups: glycine and alanine; valine, isoleucine, and leucine; aspartic acid and glutamic acid; asparagine, glutamine, serine and threonine; lysine, histidine and arginine; and phenylalanine and tyrosine. In some embodiments, a protein includes an antibody or a soluble receptor. In embodiments, a soluble receptor is ACVR2 (e.g., ACVR2B). In some embodiments, the nucleic acid is one that encodes a protein, such as dystrophin, microdystrophin, or minidystrophin. In embodiments, a nucleic acid is an antisense oligomer or a siRNA. In some embodiments, an antisense oligomer is a modified antisense oligomer as described herein. 
     As used herein, the term “antibody” refers to a whole antibody comprising two light chain polypeptides and two heavy chain polypeptides. Whole antibodies include different antibody isotypes including IgM, IgG, IgA, IgD, and IgE antibodies. The term “antibody” includes a polyclonal antibody, a monoclonal antibody, a chimerized or chimeric antibody, a humanized antibody, a primatized antibody, a deimmunized antibody, and a fully human antibody. The antibody can be made in or derived from any of a variety of species, e.g., mammals such as humans, non-human primates (e.g., orangutan, baboons, or chimpanzees), horses, cattle, pigs, sheep, goats, dogs, cats, rabbits, guinea pigs, gerbils, hamsters, rats, and mice. The antibody can be a purified or a recombinant antibody. 
     As used herein, the term “antibody fragment,” “antigen-binding fragment,” or similar terms refer to a fragment of an antibody that retains the ability to bind to a target antigen and inhibit the activity of the target antigen. Such fragments include, e.g., a single chain antibody, a single chain Fv fragment (scFv), an Fd fragment, an Fab fragment, an Fab′ fragment, or an F(ab′)2 fragment. A scFv fragment is a single polypeptide chain that includes both the heavy and light chain variable regions of the antibody from which the scFv is derived. In addition, intrabodies, minibodies, triabodies, and diabodies are also included in the definition of antibody and are compatible for use in the methods described herein. See, e.g., Todorovska et al. (2001) J Immunol Methods 248(1):47-66; Hudson and Kortt (1999) J Immunol Methods 231(1):177-189; Poljak (1994) Structure 2(12):1121-1123; Rondon and Marasco (1997) Annual Review of Microbiology 51:257-283, each of which are incorporated herein by reference in their entirety. 
     As used herein, the term “antibody fragment” also includes, e.g., single domain antibodies such as camelized single domain antibodies. See, e.g., Muyldermans et al. (2001) Trends Biochem Sci 26:230-235; Nuttall et al. (2000) Curr Pharm Biotech 1:253-263; Reichmann et al. (1999) J Immunol Meth 231:25-38; PCT application publication nos. WO 94/04678 and WO 94/25591; and U.S. Pat. No. 6,005,079, each of which are incorporated herein by reference in their entirety. In some embodiments, the disclosure provides single domain antibodies comprising two VH domains with modifications such that single domain antibodies are formed. 
     In some embodiments, an antigen-binding fragment includes the variable region of a heavy chain polypeptide and the variable region of a light chain polypeptide. In some embodiments, an antigen-binding fragment described herein comprises the CDRs of the light chain and heavy chain polypeptide of an antibody. 
     Myostatin, also referred to as growth differentiation factor 8 (GDF-8), belongs to the transforming growth factor-beta (TGF-β) superfamily. Myostatin is a protein encoded by the MSTN gene. The myostatin amino acid sequence is MQKLQLCVYIYLFMLIVAGPVDLNENSEQKENVEKEGLCNACTWRQNTKSSRIEAIKIQ ILSKLRLETAPNISKDVIRQLLPKAPPLRELIDQYDVQRDDSSDGSLEDDDYHATTETIIT MPTESDFLMQVDGKPKCCFFKFSSKIQYNKVVKAQLWIYLRPVETPTTVFVQILRLIKP MKDGTRYTGIRSLKLDMNPGTGIWQSIDVKTVLQNWLKQPESNLGIEIKALDENGHDL AVTFPGPGEDGLNPFLEVKVTDTPKRSRRDFGLDCDEHSTESRCCRYPLTVDFEAFGWD WIIAPKRYKANYCSGECEFVFLQKYPHTHLVHQANPRGSAGPCCTPTKMSPINMLYFNG KEQIIYGKIPAMVVDRCGCS (SEQ ID NO: 3502). The MSTN gene is largely expressed in human skeletal muscle and acts as a negative regulator of muscle growth. For example, in mice engineered to lack the myostatin gene demonstrate the development of twice the muscle mass of normal mice (McPherron et al., (1997), Nature 387:83-90). 
     In embodiments, a myostatin therapeutic is capable of suppressing one or both of myostatin activity and myostatin expression in a subject. A myostatin therapeutic may be a therapeutic that targets myostatin pre-mRNA and interferes with transcription of the myostatin pre-mRNA to mature mRNA. In embodiments, a myostatin therapeutic is capable of inducing exon skipping during the processing of human myostatin pre-mRNA. In embodiments, a myostatin therapeutic induces skipping of exon 2 in myostatin pre-mRNA and inhibits the expression of exon 2 containing myostatin pre-mRNA. A myostatin therapeutic may be a therapeutic that targets myostatin protein and interferes with the myostatin protein binding with the myostatin receptor. A myostatin therapeutic protein may be an anti-myostatin antibody, for example anti-GDF8 (Abcam, Cambridge Mass.), Domagrozumab (PF-06252616; Pfizer Inc.); Stamulumab (Cambridge Antibody Technology); PF-3446879 (Pfizer Inc.); Landogrozumab (LY-2495655; Eli Lilly); or Trevogrumab (REGN-103; Regeneron). In embodiments, a myostatin therapeutic may be a soluble receptor where the soluble receptor is ACVR2 (e.g., ACVR2B; MTAPWVALALLWGSLCAGSGRGEAETRECIYYNANWELERTNQSGLERCEGEQDKRL HCYASWRNSSGTIELVKKGCWLDDFNCYDRQECVATEENPQVYFCCCEGNFCNERFTH LPEAGGPEVTYEPPPTAPTLLTVLAYSLLPIGGLSLIVLLAFWMYRHRKPPYGHVDIHED PGPPPPSPLVGLKPLQLLEIKARGRFGCVWKAQLMNDFVAVKIFPLQDKQSWQSEREIFS TPGMKHENLLQFIAAEKRGSNLEVELWLITAFHDKGSLTDYLKGNIITWNELCHVAETM SRGLSYLHEDVPWCRGEGHKPSIAHRDFKSKNVLLKSDLTAVLADFGLAVRFEPGKPPG DTHGQVGTRRYMAPEVLEGAINFQRDAFLRIDMYAMGLVLWELVSRCKAADGPVDEY MLPFEEEIGQHPSLEELQEVVVHKKMRPTIKDHWLKHPGLAQLCVTIEECWDHDAEAR LSAGCVEERVSLIRRSVNGTTSDCLVSLVTSVTNVDLPPKESSI; SEQ ID NO: 3503). In some embodiments, the soluble receptor (e.g., ACVR2B) is conjugated to a heterologous moiety, e.g., a moiety that increases the circulatory half-life of the therapeutic in a subject. In some embodiments, the moiety is the Fc portion of an immunoglobulin (e.g., a human IgG Fc). In some embodiments, the moiety is a polyethylene glycol moiety. In some embodiments, the moiety comprises all or a portion of an albumin polypeptide (e.g., human albumin). In some embodiments, the myostatin therapeutic is a human ACVR2-Fc fusion, e.g., ramatercept (Acceleron). A myostatin therapeutic includes a nucleic acid where the nucleic acid is selected from an antisense oligomer and a siRNA. An antisense oligomer may be a modified myostatin antisense oligomer as described herein. In some embodiments, the myostatin therapeutic is a small molecule, such as OSX-200 (Ossianix Inc) or SRK-015 (Scholar Rock Inc.). 
     Antagonists of myostatin useful in the methods and compositions described herein include, e.g., agents that bind to directly to myostatin (GDF-8), such as anti-myostatin antibodies. Such antibodies are known in the art and described in, e.g., International Patent Application Publication No. WO2006116269 (Pfizer), U.S. Pat. No. 8,066,996 (Eli Lilly), U.S. Pat. No. 7,807,159 (Amgen), U.S. Pat. Nos. 6,096,506, and 6,468,535, the disclosures of each of which are incorporated herein by reference in their entirety. Myostatin antagonists also include soluble Activin receptor proteins, or fusion protein comprising soluble Activin proteins (e.g., ACVR2-Fc fusion proteins). Soluble Activin receptor proteins are described in, e.g., International Patent Application Publication No. WO 2010129406 (Johns Hopkins University), U.S. Patent Application Publication No. 20090005308 (Acceleron), International Patent Application Publication No. WO 2008/097541 (Acceleron), and International Patent Application Publication No. WO 2010019261 (Acceleron), the disclosures of each of which are incorporated herein by reference in their entirety. In some embodiments, the myostatin antagonist is a nucleic acid that inhibits expression of myostatin, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi) against myostatin. Such molecules are described in, e.g., U.S. Patent Application Publication No. 20050124566 and U.S. Pat. No. 7,887,793, the disclosures of each of which are incorporated herein by reference in their entirety. In some embodiments, the nucleic acids inhibit the promoter of myostatin to thereby inhibit myostatin expression, as described in, e.g., U.S. Pat. No. 6,284,882 to Abbott Laboratories. Inhibitors of myostatin also include agents that inhibit myostatin signaling via its receptor, such as anti-ACVR2B antibodies (see, e.g., U.S. Patent Application Publication No. 20100272734 (Novartis) and International Patent Application Publication No. WO2014172448 (Anaptysbio)). Yet additional exemplary inhibitors of myostatin are described in International Patent Application Publication No. WO 2006/083183. 
     In some embodiments, a dystrophin therapeutic is administered first in time and the myostatin therapeutic is administered second in time. For example, the dystrophin therapeutic is administered for a time sufficient to promote, restore, and/or increase expression of functional dystrophin protein in muscle of the subject to which the therapeutic is administered. Subsequently, the myostatin therapeutic is administered to the subject for a time sufficient to, e.g., enhance muscle mass, strength, and/or elasticity in the subject. In embodiments, a dystrophin therapeutic is capable of increasing expression of dystrophin in a subject. A dystrophin therapeutic may increase the expression of dystrophin or a truncated form of dystrophin that is functional or semi-functional. A truncated form of dystrophin includes, but is not limited to, micro-dystrophin and mini-dystrophin (disclosed in EP Patent no. 2125006, which is hereby incorporated by reference in its entirety). A dystrophin therapeutic may be a therapeutic that targets dystrophin pre-mRNA and modulates the transcription of the dystrophin pre-mRNA to mature mRNA, for example, a modified antisense oligomer as described herein. In embodiments, a dystrophin therapeutic is capable of inducing exon skipping during processing of human dystrophin pre-mRNA. In embodiments, a targeted dystrophin pre-mRNA may have one or more genetic mutations. A dystrophin therapeutic induces exon skipping such that one or more exons containing one or more genetic mutations are removed from the dystrophin pre-mRNA during processing to mature mRNA. The resulting truncated mRNA may be translated into a functional or semi-functional dystrophin protein. 
     In some embodiments, the dystrophin therapeutic is or comprises a nucleic acid encoding a functional dystrophin protein, e.g., a microdystrophin or minidystrophin protein. In some embodiments, the nucleic acid is introduced into muscle cells of the subject by means of viral delivery. In some embodiments, expression of the functional dystrophin protein from the nucleic acid is driven by a muscle-specific promoter, such as the promoter for muscle creatine kinase (MCK). The use of viral vectors comprising a functional dystrophin protein for DMD gene therapy has been described in, e.g., Shin et al. (2013) Mol Ther 21(4):750-757; Rodino-Klapac et al. (2011) Methods Mol Biol 709:287-298; Okada et al. (2013) Pharmaceuticals 6(7):813-836; Rodino-Klapac et al. (2010) Mol Ther 18(1):109-117; Vincent et al. (1993) Nature Genetics 5:130-134; Xu et al. (2007) Neuromusc Disorders 17: 209-220; Martin et al. (2009) Am J Physiol Cell Physiol 296: 476-488; International Patent Application Publication No. WO 2009/088895, and U.S. Patent Application Publication Nos. 2010003218 and 20140323956, the disclosures of each of which are incorporated herein by reference in their entirety. One of skill in the art is also well aware of other vector systems that can be used to deliver a transgene to cells of interest, e.g., U.S. Pat. No. 5,707,618; Verhaart et al. (2012) Curr Opin Neurol 25(5):588-596; Odom et al. (2011) Mol Ther 19(1):36-45; and Koppanati et al. (2010) Gene Ther 17(11):1355-1362. Ongoing clinical studies evaluating transgenic delivery of functional dystrophin protein include, e.g., the studies having U.S. ClinicalTrials.gov identifiers: NCT02376816 (Nationwide Children&#39;s Hospital) and NCT00428935 (Nationwide Children&#39;s Hospital) as well as the trial described by Bowles et al. (2012) Mol Ther 20(2):443-455. 
     One of skill in the art is well aware that various mutations in the dystrophin gene are amenable to therapeutic exon skipping. For example, non-limiting examples of mutations in the following exons are amenable to exon 51 skipping include, e.g.: 45-50, 47-50, 48-50, 49-50, 50, 52, 52-63 (Leiden Duchenne muscular dystrophy mutation database, Leiden University Medical Center, The Netherlands). Determining whether a patient has a mutation in the DMD gene that is amenable to exon skipping is also well within the purview of one of skill in the art (see, e.g., Aartsma-Rus et al. (2009) Hum Mut 30:293-299 and Abbs et al. (2010) Neuromusc Disorders 20:422-427, the disclosures of each of which are incorporated herein by reference in their entirety). 
     Eteplirsen (see e.g., U.S. Pat. No. 7,807,816, incorporated herein by reference in its entirety) has been the subject of clinical studies to test its safety and efficacy, and clinical development is ongoing. Eteplirsen is a phosphorodiamidate mopholino (PMO) antisense oligonucleotide. In some embodiments, the dystrophin therapeutic is eteplirsen. “Eteplirsen”, also known as “AVN-4658” is a PMO having the base sequence 5′-CTCCAACATCAAGGAAGATGGCATTTCTAG-3′ (SEQ ID NO: 76). Eteplirsen is registered under CAS Registry Number 1173755-55-9. Chemical names include: RNA, [P-deoxy-P-(dimethyl amino)](2′,3′-dideoxy-2′,3′-imino-2′,3′-seco)(2′a→5′)(C-m5U-C-C-A-A-C-A-m5U-C-A-A-G-G-A-A-G-A-m5U-G-G-C-A-m5U-m5U-m5U-C-m5U-A-G) (SEQ ID NO: 263), 5′-[P[4-[[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]carbonyl]-1-piperazinyl]-N,N-dimethylphosphonamidate] and P,2′,3′-trideoxy-P-(dimethylamino)-5′-O-{P-[4-(10-hydroxy-2,5,8-trioxadecanoyl)piperazin-1-yl]-N,N-dimethylphosphonamidoyl}-2′,3′-imino-2′,3′-secocytidylyl-(2′a→5′)-P,3′-dideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secothymidylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secocytidylyl-(2′a→5)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secocytidylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secocytidylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5′)-P,3′-dideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secothymidylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secocytidylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoguanylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoguanylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoguanylyl-(2′a→5)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5′)-P,3′-dideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secothymidylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoguanylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoguanylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secocytidylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5′)-P,3′-dideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secothymidylyl-(2′a→5′)-P,3′-dideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secothymidylyl-(2′a→5′)-P,3′-dideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secothymidylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secocytidylyl-(2′a→5′)-P,3′-dideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secothymidylyl-(2′a→5′)-P,2′,3′-trideoxy-P-(dimethylamino)-2′,3′-imino-2′,3′-secoadenylyl-(2′a→5′)-2′,3′-dideoxy-2′,3′-imino-2′,3′-secoguanosine. 
     Eteplirsen has the following structure: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     “Dystrophin” is a rod-shaped cytoplasmic protein, and a vital part of the protein complex that connects the cytoskeleton of a muscle fiber to the surrounding extracellular matrix through the cell membrane, encoded by the dystrophin (i.e., DMD) gene. Dystrophin contains multiple functional domains. For instance, dystrophin contains an actin binding domain at about amino acids 14-240 and a central rod domain at about amino acids 253-3040. This large central domain is formed by 24 spectrin-like triple-helical elements of about 109 amino acids, which have homology to alpha-actinin and spectrin. The repeats are typically interrupted by four proline-rich non-repeat segments, also referred to as hinge regions. Repeats 15 and 16 are separated by an 18 amino acid stretch that appears to provide a major site for proteolytic cleavage of dystrophin. The sequence identity between most repeats ranges from 10-25%. One repeat contains three alpha-helices: 1, 2 and 3. Alpha-helices 1 and 3 are each formed by 7 helix turns, probably interacting as a coiled-coil through a hydrophobic interface. Alpha-helix 2 has a more complex structure and is formed by segments of four and three helix turns, separated by a Glycine or Proline residue. Each repeat is encoded by two exons, typically interrupted by an intron between amino acids 47 and 48 in the first part of alpha-helix 2. The other intron is found at different positions in the repeat, usually scattered over helix-3. Dystrophin also contains a cysteine-rich domain at about amino acids 3080-3360), including a cysteine-rich segment (i.e., 15 Cysteines in 280 amino acids) showing homology to the C-terminal domain of the slime mold (Dictyostelium discoideum) alpha-actinin. The carboxy-terminal domain is at about amino acids 3361-3685. 
     The amino-terminus of dystrophin binds to F-actin and the carboxy-terminus binds to the dystrophin-associated protein complex (DAPC) at the sarcolemma. The DAPC includes the dystroglycans, sarcoglycans, integrins and caveolin, and mutations in any of these components cause autosomally inherited muscular dystrophies. The DAPC is destabilized when dystrophin is absent, which results in diminished levels of the member proteins, and in turn leads to progressive fibre damage and membrane leakage. In various forms of muscular dystrophy, such as Duchenne&#39;s muscular dystrophy (DMD) and Becker&#39;s muscular dystrophy (BMD), muscle cells produce an altered and functionally defective form of dystrophin, or no dystrophin at all, mainly due to mutations in the gene sequence that lead to incorrect splicing. The predominant expression of the defective dystrophin protein, or the complete lack of dystrophin or a dystrophin-like protein, leads to rapid progression of muscle degeneration, as noted above. In this regard, a “defective” dystrophin protein may be characterized by the forms of dystrophin that are produced in certain subjects with DMD or BMD, as known in the art, or by the absence of detectable dystrophin. 
     The term “functional” in reference to a dystrophin protein includes those proteins derived from an mRNA transcript containing sequences corresponding to all of exons 1 to 79 of a dystrophin gene, also referred to as a wildtype protein. A functional dystrophin protein refers generally to a dystrophin protein having sufficient biological activity to reduce the progressive degradation of muscle tissue that is otherwise characteristic of Duchenne muscular dystrophy, typically as compared to the altered or “defective” form of dystrophin protein that is present in certain subjects with DMD or related disorders. A functional dystrophin protein may have about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% (including all integers in between) of the in vitro or in vivo biological activity of wildtype dystrophin, as measured according to routine techniques in the art. As one example, dystrophin-related activity in muscle cultures in vitro can be measured according to myotube size, myofibril organization (or disorganization), contractile activity, and spontaneous clustering of acetylcholine receptors (see, e.g., Brown et al., Journal of Cell Science. 112:209-216, 1999). Animal models are also valuable resources for studying the pathogenesis of disease, and provide a means to test dystrophin-related activity. Two of the most widely used animal models for DMD research are the mdx mouse and the golden retriever muscular dystrophy (GRMD) dog, both of which are dystrophin negative (see, e.g., Collins &amp; Morgan, Int J Exp Pathol 84: 165-172, 2003). These and other animal models can be used to measure the functional activity of various dystrophin proteins. Included are truncated forms of dystrophin, such as those forms that are produced by certain of the antisense oligomer compounds of the present invention. 
     The term “functional” or “semi-functional” dystrophin protein includes those proteins derived from an mRNA transcript containing sequences corresponding to a truncated form of the transcript, for example, a dystrophin mRNA transcript having less than all of exons 1 to 79 of a dystrophin gene. In other words, a truncated form of a dystrophin mRNA may exclude one or more exons of a corresponding dystrophin gene. A truncated form of a dystrophin mRNA may express a truncated or shortened form of a dystrophin protein, also referred to as a microdystrophin protein. 
     The term “functional” in reference to a myostatin protein includes those proteins derived from an mRNA transcript containing all sequences corresponding to exon 1, exon 2 and exon 3 of a myostatin gene, also referred to as a wildtype protein. 
     A non-functional, dysfunctional or inactive myostatin protein includes a protein derived from a myostatin mRNA transcript missing all or any portion of the full gene corresponding to the sequence of exon 1, exon 2 and exon 3, or that contains all or a portion of the sequences corresponding to intron 1, intron 2, or other intron sequences, or where the non-functional state relates to missing functional elements as derived from a respective exon, or as otherwise derived from the inclusion of a respective intron, including partial or full sequences thereof. A non-functional, dysfunctional or inactive myostatin protein includes a protein derived from a myostatin mRNA transcript which excludes exon 2, for example, and/or having reduced functionality relative to the wildtype myostatin protein. 
     Thus, in various embodiments, the presence of, expression of, or increased expression of functional or semi-functional dystrophin protein may be determined, for example, by western blot analysis and dystrophin gene expression of, for example, DMD patient derived muscle cells treated with a modified antisense oligomer and/or a therapeutic of the present disclosure. In various embodiments, treatment of DMD muscle cells or a subject in need of treatment of DMD with a modified antisense oligomer and/or therapeutic of the disclosure may result in expression of functional dystrophin protein in an amount that is, for example, about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%, of the normal amount of dystrophin protein expressed in normal cells or a normal subject. 
     In various embodiments, the functionality of dystrophin or truncated dystrophin protein expressed by a tissue or a subject in need of treatment of DMD may be determined by immunohistochemical analysis of, for example, the number of muscle fibers, the increase in muscle mass, the percent of muscle fiber with centralized nuclei, and the amount of functional dystrophin protein as compared to untreated equivalents. The functionality of dystrophin or truncated dystrophin protein of a subject in need of treatment of DMD may be further analyzed by physical and physiological tests such as motor function tests including measurements of muscle mass and grip strength. 
     In some embodiments, the dystrophin therapeutic restores dystrophin expression in cells of interest. The term “restoration” of dystrophin synthesis or production refers generally to the production of a dystrophin protein including truncated forms of dystrophin in a patient with muscular dystrophy following treatment with eteplirsen as described herein. In some embodiments, treatment results in an increase in novel dystrophin production in a patient by 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% (including all integers in between). In some embodiments, treatment increases the number of dystrophin-positive fibers to at least 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 95% to 100% of normal in the subject. In other embodiments, treatment increases the number of dystrophin-positive fibers to about 20% to about 60%, or about 30% to about 50% of normal in the subject. The percent of dystrophin-positive fibers in a patient following treatment can be determined by a muscle biopsy using known techniques. For example, a muscle biopsy may be taken from a suitable muscle, such as the biceps brachii muscle in a patient. 
     Analysis of the percentage of positive dystrophin fibers may be performed pre-treatment and/or post-treatment or at time points throughout the course of treatment. In some embodiments, a post-treatment biopsy is taken from the contralateral muscle from the pre-treatment biopsy. Pre- and post-treatment dystrophin expression studies may be performed using any suitable assay for dystrophin. In one embodiment, immunohistochemical detection is performed on tissue sections from the muscle biopsy using an antibody that is a marker for dystrophin, such as a monoclonal or a polyclonal antibody. For example, the MANDYS106 antibody can be used which is a highly sensitive marker for dystrophin. Any suitable secondary antibody may be used. 
     In some embodiments, the percent dystrophin-positive fibers are calculated by dividing the number of positive fibers by the total fibers counted. Normal muscle samples have 100% dystrophin-positive fibers. Therefore, the percent dystrophin-positive fibers can be expressed as a percentage of normal. To control for the presence of trace levels of dystrophin in the pretreatment muscle as well as revertant fibers a baseline can be set using sections of pre-treatment muscles from each patient when counting dystrophin-positive fibers in post-treatment muscles. This may be used as a threshold for counting dystrophin-positive fibers in sections of post-treatment muscle in that patient. In other embodiments, antibody-stained tissue sections can also be used for dystrophin quantification using Bioquant image analysis software (Bioquant Image Analysis Corporation, Nashville, Tenn.). The total dystrophin fluorescence signal intensity can be reported as a percentage of normal. In addition, Western blot analysis with monoclonal or polyclonal anti-dystrophin antibodies can be used to determine the percentage of dystrophin positive fibers. For example, the anti dystrophin antibody NCL-Dysl from Novacastra may be used. Dystrophin production can also be measured by reverse-transcription polymerase chain reaction (RT-PCR). Primers can be designed to measure dystrophin genes that will produce a functional dystrophin protein. The percentage of dystrophin-positive fibers can also be analyzed by determining the expression of the components of the sarcoglycan complex (□□□) and/or neuronal NOS. 
     In some embodiments, treatment slows or reduces the progressive respiratory muscle dysfunction and/or failure in patients with DMD that would be expected without treatment. In some embodiments, treatment stabilizes respiratory muscle function in patients with DMD. In one embodiment, treatment with eteplirsen may reduce or eliminate the need for ventilation assistance that would be expected without treatment. In one embodiment, measurements of respiratory function for tracking the course of the disease, as well as the evaluation of potential therapeutic interventions include Maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP) and forced vital capacity (FVC). MIP and MEP measure the level of pressure a person can generate during inhalation and exhalation, respectively, and are sensitive measures of respiratory muscle strength. MIP is a measure of diaphragm muscle weakness. 
     In some embodiments, treatment may stabilize, maintain, improve or increase walking ability (e.g., stabilization of ambulation) in the subject. In some embodiments, treatment maintains, increases, or reduces loss of a stable walking distance in a patient, as measured by, for example, the 6 Minute Walk Test (6MWT), described by McDonald, et al. (Muscle Nerve, 2010; 42:966-74; Muscle Nerve, 2010; 41:500-10, the contents of which are herein incorporated by reference in its entirety). The 6MWT is a clinically meaningful endpoint focused on ambulation that characterizes changes in walking function over time as an expression of changes in disease state. 
     A change in the 6 Minute Walk Distance (6MWD) may be expressed as an absolute value, a percentage change or a change in the %-predicted value. The performance of a DMD patient in the 6MWT relative to the typical performance of a healthy peer can be determined by calculating a %-predicted value. For example, the %-predicted 6MWD may be calculated using the following equation for males: 196.72+(39.81×age)−(1.36×age2)+(132.28×height in meters). For females, the %-predicted 6MWD may be calculated using the following equation: 188.61+(51.50×age)−(1.86×age2)+(86.10×height in meters) (Henricson et al. PLoS Curr., 2012, version 2, the contents of which are herein incorporated by reference in its entirety). 
     Ambulation can be measured through various methods, including the North Star Ambulatory Assessment (NSAA). The NSAA was developed by the Physiotherapy Assessment and Evaluation Group of the North Start Clinical Network to assess ambulant boys with DMD, and provides a list of activities that are scored from 2-0, with 2 being normal and 0 being “unable to achieve independently” (2006-2011 MDC/North Star Clinical Network). These activities range from standing for a minimum of 3 seconds to climbing up and down a box to running. In certain embodiments, treatment with eteplirsen may maintain, stabilize, increase, or improve ambulation, for example, as determined by the NSAA. 
     In the present case, therapeutic agents, including modified antisense oligomers are used to induce a decrease in myostatin mRNA containing exon 2, resulting in an amelioration of Duchenne muscular dystrophy symptoms (e.g. reduction of functional myostatin protein) in the range of about 30% to about 100% or the percentages disclosed above with regard to functionality, as compared to non-treatment. Such amelioration of symptoms may be observed on a micro level (e.g. reduction of myostatin protein expression measured by, for example, immunohistochemistry, immunofluorescence, western-blot analyses; increase of muscle growth; restoration of muscle function) and physiological level (e.g. improvement of motor function assessed by physical examination). 
     Modified antisense oligomers are used to induce exon skipping during the processing of dystrophin pre-mRNA where the dystrophin pre-mRNA includes exons having one or more genetic mutations, or in which one or more regions of the dystrophin gene have been deleted, resulting in an amelioration of symptoms related to Duchenne muscular dystrophy and related disorders (e.g. restoration of functional or semi-functional dystrophin protein). Functional or semi-functional dystrophin protein may be increased in the range of about 30% to about 100% or the percentages disclosed above with regard to functionality, as compared to non-treatment. Such amelioration of symptoms may be observed on a micro level (e.g. increase of dystrophin protein expression measured by, for example, immunohistochemistry, immunofluorescence, western-blot analyses; increase of muscle growth; restoration of muscle function) and physiological level (e.g. improvement of motor function assessed by physical examination). 
     The term “nucleotide” refers to a naturally occurring nucleotide comprising a nucleobase, a sugar and at least one phosphate group (e.g., a phosphodiester linking group). 
     The term “nucleotide analog” refers to a derivative of, or modification to, a naturally occurring nucleotide, for example, a nucleotide comprising at least one modification. Such modifications may include at least one of (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing. The skilled practitioner will appreciate that where a modification is specified with respect to any one component of a nucleotide subunit (e.g., a modified sugar), the unspecified portion(s) of the nucleotide subunit may remain unmodified (e.g., an unmodified internucleoside linkage, an unmodified nucleobase). 
     The terms “oligonucleotide,” “oligomer,” “oligo,” “antisense oligonucleotide,” “antisense oligomer,” “modified antisense oligomer” and “antisense oligo,” and other appropriate combinations and derivations thereof, refer to linear sequences of nucleotides, or nucleotide analogs, where one or more nucleobases may hybridize to a portion of a target RNA against which the oligomer is directed, referred to as a target sequence, by Watson-Crick base pairing, to form an oligomer:RNA heteroduplex within the target sequence. Specifically, the terms “antisense,” “oligonucleotide,” “oligomer,” “oligo” and “compound” may be used in various combinations and interchangeably to refer to such an oligomer. Cyclic subunits comprising portions of the nucleotides may be based on ribose or another pentose sugar, sugar analog or, in certain embodiments may be a modified sugar, for example, a morpholino group (see description of morpholino-based oligomers below). 
     The term “modified,” “non-naturally-occurring,” or “analogs,” and other appropriate combinations and derivatives thereof, when referring to oligomers, refer to oligomers having one or more nucleotide subunits having at least one modification selected from (i) a modified internucleoside linkage, e.g., an internucleoside linkage other than the standard phosphodiester linkage found in naturally-occurring oligonucleotides, (ii) modified sugar moieties, e.g., moieties other than ribose or deoxyribose moieties found in naturally occurring oligonucleotides, or (iii) a combination of the foregoing. In various embodiments, a modified internucleoside linkage is selected from a phosphorothioate internucleoside linkage, a phosphoramidate internucleoside linkage, a phosphorodiamidate internucleoside linkage, and a phosphorotriamidate internucleoside linkage. In further embodiments, the phosphorodiamidate internucleoside linkage comprises a phosphorous atom that is covalently bonded to a (1,4-piperazin)-1-yl moiety, a substituted (1,4-piperazin)-1-yl moiety, a 4-aminopiperidin-1-yl moiety, or a substituted 4-aminopiperidin-1-yl moiety. In various embodiments, the modified sugar moiety is selected from a peptide nucleic acid (PNA) subunit, a locked nucleic acid (LNA) subunit, a 2′O,4′C-ethylene-bridged nucleic acid (ENA) subunit, a tricyclo-DNA (tc-DNA) subunit, a 2′ O-methyl subunit, a 2′ O-methoxyethyl subunit, a 2′-fluoro subunit, a 2′-O-[2-(N-methylcarbamoyl)ethyl]subunit, and a morpholino subunit. 
     A modification to the internucleoside linkage may be between at least two sugar and/or modified sugar moieties of an oligomer. Nucleotide analogs support bases capable of hydrogen bonding by Watson-Crick base pairing to naturally occurring oligonucleotide bases, where the analog presents the bases in a manner to permit such hydrogen bonding in a sequence-specific fashion between the oligomer analog molecule and bases in the naturally occurring oligonucleotide (e.g., single-stranded RNA or single-stranded DNA). Exemplary analogs are those having a substantially uncharged, phosphorus containing internucleoside linkages. 
     A “nuclease-resistant” oligomer refers to one whose internucleoside linkage is substantially resistant to nuclease cleavage, in non-hybridized or hybridized form; by common extracellular and intracellular nucleases in the body (for example, by exonucleases such as 3′-exonucleases, endonucleases, RNase H); that is, the oligomer shows little or no nuclease cleavage under normal nuclease conditions in the body to which the oligomer is exposed. A “nuclease-resistant heteroduplex” refers to a heteroduplex formed by the binding of a modified antisense oligomer to its complementary target, such that the heteroduplex is substantially resistant to in vivo degradation by intracellular and extracellular nucleases, which are capable of cutting double-stranded RNA/RNA or RNA/DNA complexes. A “heteroduplex” refers to a duplex between a modified antisense oligomer and the complementary portion of a target RNA. For example, a nuclease-resistant oligomer may be a modified antisense oligomer as described herein. 
     The terms “nucleobase” (Nu), “base pairing moiety” or “base” are used interchangeably to refer to a purine or pyrimidine base found in naturally occurring, or “native” DNA or RNA (e.g., uracil, thymine, adenine, cytosine, and guanine), as well as analogs of these naturally occurring purines and pyrimidines, that may confer improved properties, such as binding affinity to the oligomer. Exemplary analogs include hypoxanthine (the base component of the nucleoside inosine); 2, 6-diaminopurine; 5-methyl cytosine; C5-propynyl-modified pyrimidines; 10-(9-(aminoethoxy)phenoxazinyl) (G-clamp) and the like. 
     Further examples of base pairing moieties include, but are not limited to, uracil, thymine, adenine, cytosine, guanine and hypoxanthine (inosine) having their respective amino groups protected by acyl protecting groups, 2-fluorouracil, 2-fluorocytosine, 5-bromouracil, 5-iodouracil, 2,6-diaminopurine, azacytosine, pyrimidine analogs such as pseudoisocytosine and pseudouracil and other modified nucleobases such as 8-substituted purines, xanthine, or hypoxanthine (the latter two being the natural degradation products). The modified nucleobases disclosed in Chiu and Rana, R N A, 2003, 9, 1034-1048, Limbach et al. Nucleic Acids Research, 1994, 22, 2183-2196 and Revankar and Rao, Comprehensive Natural Products Chemistry, 1999, vol. 7, 313, are also contemplated, the contents of which are incorporated herein by reference. 
     Further examples of base pairing moieties include, but are not limited to, expanded-size nucleobases in which one or more benzene rings has been added. Nucleic base replacements are described in the following examples: the Glen Research catalog (www.glenresearch.com); Krueger A T et al., Acc. Chem. Res., 2007, 40, 141-150; Kool, E T, Acc. Chem. Res., 2002, 35, 936-943; Benner S. A., et al., Nat. Rev. Genet., 2005, 6, 553-543; Romesberg, F. E., et al., Curr. Opin. Chem. Biol., 2003, 7, 723-733; Hirao, I., Curr. Opin. Chem. Biol., 2006, 10, 622-627, the contents of each example are incorporated herein by reference. These are contemplated as useful for the synthesis of various oligomers described herein. Examples of expanded-size nucleobases are shown below: 
     
       
         
         
             
             
         
       
     
     A nucleobase covalently linked to a ribose, sugar analog, modified sugar or morpholino comprises a nucleoside. “Nucleotides” comprise a nucleoside together with at least one linking phosphate group. The phosphate groups comprise covalent linkages to adjacent nucleosides form an oligomer. Thus, the phosphate group of the nucleotide is commonly referred to as forming an “internucleoside linkage.” Accordingly, a nucleotide comprises a nucleoside as further described herein and an internucleoside linkage. In some embodiments, a modified antisense oligomer of the disclosure comprises subunits wherein a “subunit” includes naturally occurring nucleotides, nucleotide analogs as described herein, and combinations thereof. In certain embodiments, a modified antisense oligomer of the disclosure comprises subunits wherein at least one subunit is a nucleotide analog. 
     The terms “sequence identity,” “sequence homology,” and “complementarity” (e.g. a “sequence 50% identical to,” a “sequence 50% homologous to,” and “a sequence 50% complementary to”) in the context of nucleic acids refer to the extent that a sequence is identical on a nucleotide-by-nucleotide basis over a window of comparison. A “percentage identity,” “percentage homology,” and “percentage complementary to” may be calculated by comparing two optimally aligned sequences over the window of comparison, determining the number of positions at which the identical nucleic acid base (e.g., A, T, C, G, I) occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the window of comparison (i.e., the window size), and multiplying the result by 100 to yield the percentage of sequence identity. Optimal alignment of sequences for aligning a comparison window may be conducted by computerized implementations of algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package Release 7.0, Genetics Computer Group, 575 Science Drive Madison, Wis., USA) or by inspection and the best alignment (i.e., resulting in the highest percentage homology over the comparison window) generated by any of the various methods selected. Reference also may be made to the BLAST family of programs as for example disclosed by Altschul et al., Nucl. Acids Res. 25:3389, 1997. In various embodiments, a modified antisense oligomer of the disclosure may have at least 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100% sequence identity with a targeting sequence in Table 1 (SEQ ID NOS: 1 to 3) and Table 2 (SEQ ID NOS: 4-15). 
     As used herein, a targeting sequence of an oligomer “specifically hybridizes” to a target region of an oligonucleotide if the oligomer hybridizes to the target region under physiological conditions, with a melting point (Tm) substantially greater than 40° C., 45° C., 50° C., and in various embodiments, 60° C.−80° C. or higher. Such hybridization preferably corresponds to stringent hybridization conditions. At a given ionic strength and pH, the Tm is the temperature at which 50% of a targeting sequence hybridizes to a complementary sequence in a target region. Such hybridization may occur with “near” or “substantial” complementarity of the modified antisense oligomer to the target region, as well as with exact complementarity. In some embodiments, an oligomer may hybridize to a target region at about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or 100%. 
     As used herein, the term “subunit” refers to a naturally occurring nucleotide or a naturally occurring nucleotide comprising at least one modification. A modification may comprise at least one of (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing. In further embodiments, a modification may include a modified nucleobase. 
     As used herein, the term “sufficient length” refers to a modified antisense oligomer that is complementary to at least 20 to 50 contiguous nucleobases in a target region within a pre-mRNA, where such complementarity may be completely internal to a target region within an exon or may span a splice junction across an intron/exon or exon/intron region. In embodiments, sufficient length may refer to a modified antisense oligomer that is complementary to at least 12, contiguous nucleobases in a target region within a pre-mRNA, where such complementarity may be completely internal to a target region within an exon or may span a splice junction across an intron/exon or exon/intron region. 
     A modified myostatin antisense oligomer may, for example, be complementary to intron 1/exon 2, exon 2 or exon 2/intron 2 of myostatin pre-mRNA. In various embodiments, the modified myostatin antisense oligomer comprises at least a number of nucleotides to be capable of specifically hybridizing to a target region of a myostatin pre-mRNA sequence. Preferably an oligomer of sufficient length is from 12 to 40 nucleotides, 12 to 30 nucleotides, 12 to 15 nucleotides, 12 to 20 nucleotides, 15 to 20 nucleotides, 15 to 22 nucleotides, 12 to 22 nucleotides in length, including all integers in between these ranges. In some embodiments, the myostatin antisense oligomer is about 12 to about 40 or about 12 to about 30 bases in length. In some embodiments, the antisense oligomer is about 12 to about 25, about 15 to about 25, or about 15 to about 20 bases in length. In some embodiments, a myostatin antisense oligomer sequence comprises at least about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 contiguous or non-contiguous bases that are complementary to the target sequences of Table 1 (e.g., SEQ ID NO: 1, SEQ ID NO: 2 or SEQ ID NO: 3, or sequences that span at least a portion of SEQ ID NO: X, SEQ ID NO: Y or SEQ ID NO: Z). 
     A modified dystrophin antisense oligomer may be complementary to a target region completely internal to exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53 or exon 55. In various embodiments, the modified dystrophin antisense oligomer comprises at least a number of nucleotides to be capable of specifically hybridizing to a target region of a dystrophin pre-mRNA sequence. Preferably an oligomer of sufficient length is from 17 to 50 nucleotides, 17 to 40 nucleotides, 14 to 25 nucleotides, 15 to 30 nucleotides, 17 to 30 nucleotides, 17 to 27 nucleotides, 10 to 27 nucleotides, 10 to 25 nucleotides, or 10 to 20 nucleotides in length, including all integers in between these ranges. In some embodiments, the antisense oligomer is about 17 to about 40 or about 10 to about 30 bases in length. In some embodiments, the antisense oligomer is about 14 to about 25 or about 17 to about 27 bases in length. In some embodiments, an antisense oligomer sequence comprises at least about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 contiguous or non-contiguous bases that are complementary to the target sequences of Table 2 (e.g., SEQ ID NOS: 4-15). 
     As used herein, the term a “subject” or a “subject in need thereof” includes a mammalian subject such as a human subject. Exemplary mammalian subjects have or are at risk for having Duchenne muscular dystrophy and related disorders. As used herein, the term “muscular dystrophy,” “Duchenne muscular dystrophy” and “related disorders” refers to a human autosomal recessive disease that is often characterized by over expression of myostatin protein or by genetic mutations in the dystrophin gene in affected individuals. In some embodiments, Duchenne muscular dystrophy and related disorders include, but are not limited to, Becker muscular dystrophy, limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, muscle wasting conditions or disorders, such as AIDS, cancer or chemotherapy related muscle wasting, and fibrosis or fibrosis-related disorders (for example, skeletal muscle fibrosis). 
     A “patient,” as used herein, includes any person that exhibits a symptom, or is at risk for exhibiting a symptom, which can be treated as described herein, such as a subject that has or is at risk for having DMD or BMD, or any of the symptoms associated with these conditions (e.g., muscle fibre loss). 
     A “pediatric patient” as used herein is a patient from age 1 to 21, inclusive. In some embodiments, the pediatric patient is a patient from age 7 to 21 (e.g., age 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or 21). In some embodiments, the pediatric patient is a patient of less than seven years of age. In some embodiments, the pediatric patient is a patient of seven years of age or older. 
     As used herein, the term “target” or “target region” refers to a region within a pre-mRNA transcript such as myostatin or dystrophin pre-mRNA. In various embodiments, a myostatin target region is a region comprising intron 1/exon 2, exon 2, or exon 2/intron 2 of the myostatin pre-mRNA. In various embodiments, a dystrophin target region is a region comprising one or more of exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53 or exon 55. 
     In various embodiments, the term “targeting sequence” refers to the sequence in the modified antisense oligomer or oligomer analog that is complementary to the target sequence in the pre-mRNA transcript. The entire sequence, or only a portion, of the modified antisense oligomer may be complementary to the target sequence. For example, in an oligomer having 12-50 bases, about 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 may contain sequences (e.g. “targeting sequences”) that are complementary to the target region within the pre-mRNA transcript. Typically, the targeting sequence is formed of contiguous bases in the oligomer, but may alternatively be formed of non-contiguous sequences that when placed together, e.g., from opposite ends of the oligomer, constitute a sequence that spans the target sequence. 
     A “targeting sequence” may have “near” or “substantial” complementarity to the target sequence and still function for its intended purpose, for example, to increase the level of dystrophin mRNA expression which excludes one or more exons having a genetic mutation, or to increase expression of functional or semi-functional dystrophin protein. In the case of myostatin, a targeting sequence may function to reduce the level of expression of exon 2 containing myostatin mRNA, or decrease expression of functional myostatin protein. Preferably, modified antisense oligomer compounds in the present disclosure have at most one mismatch with the target sequence out of 10 nucleotides, or one mismatch out of 20. Alternatively, the modified antisense oligomers herein have at least 90% sequence homology, at least 95% sequence homology, at least 99% sequence homology, or 100% sequence homology, with the exemplary target sequences as designated herein. 
     In the case of dystrophin, a targeting sequence may comprise a sequence selected from SEQ ID NOS: 76 to 3485, is selected from SEQ ID NOS: 76 to 3485, is a fragment of at least 10 contiguous nucleotides of a sequence selected from SEQ ID NOS: 76 to 3485, or is a variant having at least 90% sequence identity to a sequence selected from SEQ ID NOS: 76 to 3485, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 76 to 3485 is thymine (T), and each Y of SEQ ID NOS: 76 to 3485 is cytosine (C). In some embodiments, a targeting sequence may comprise SEQ ID NO: 76. 
     In the case of myostatin, a targeting sequence may comprise a sequence selected from SEQ ID NOS: 16 to 75, is selected from SEQ ID NOS: 16 to 75, is a fragment of at least 10 contiguous nucleotides of a sequence selected from SEQ ID NOS: 16 to 75, or is a variant having at least 90% sequence identity to a sequence selected from SEQ ID NOS: 16 to 75, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 16 to 75 is thymine (T), and each Y of SEQ ID NOS: 16 to 75 is cytosine (C). 
     In some embodiments, the myostatin targeting sequence is selected from: 
     
       
         
           
               
               
            
               
                   
                 a) 
               
            
           
           
               
            
               
                 SEQ ID NO: 71 
               
            
           
           
               
               
            
               
                   
                 (YYAGYYYAXYXXYXYYXGGXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 b) 
               
            
           
           
               
            
               
                 SEQ ID NO: 72 
               
            
           
           
               
               
            
               
                   
                 (YAYXXAYYAGYYYAXYXXYXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 c) 
               
            
           
           
               
            
               
                 SEQ ID NO: 73 
               
            
           
           
               
               
            
               
                   
                 (YYAYXXGYAXXAGAAAAXYAGY) wherein Z is 22; 
               
               
                   
                   
               
               
                   
                 d) 
               
            
           
           
               
            
               
                 SEQ ID NO: 74 
               
            
           
           
               
               
            
               
                   
                 (GYATTAGAAAATYAGYTATAAATG) wherein Z is 24; 
               
               
                   
                 and 
               
               
                   
                   
               
               
                   
                 e) 
               
            
           
           
               
            
               
                 SEQ ID NO: 75 
               
            
           
           
               
               
            
               
                   
                 (YYATYYGYTTGYATTAGAAAGTYAGY) wherein Z is 26; 
               
            
           
         
       
         
         
           
             wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 71 to 75 is thymine (T), and each Y of SEQ ID NOS: 71 to 75 is cytosine (C). 
           
         
       
    
     In various embodiments, at least one X of the targeting sequence is T. In various embodiments, each X of the targeting sequence is T. 
     In various embodiments, at least one X of the targeting sequence is U. In various embodiments, each X of the targeting sequence is U. 
     In various embodiments, at least one Y of the targeting sequence is 5 mC. In various embodiments, each Y of the targeting sequence is 5 mC. 
     In various embodiments, at least one Y of the targeting sequence is C. In various embodiments, each Y of the targeting sequence is C. 
     In various embodiments, at least one X of SEQ ID NOS: 16 to 75 and SEQ ID NOS: 76 to 3485 is T. In various embodiments, each X of SEQ ID NOS: 16 to 75 and SEQ ID NOS: 76 to 3485 is T. 
     In various embodiments, at least one X of the targeting sequence is U. In various embodiments, each X of SEQ ID NOS: 16 to 75 and SEQ ID NOS: 76 to 3485 is U. 
     In various embodiments, at least one Y of SEQ ID NOS: 16 to 75 and SEQ ID NOS: 76 to 3485 is 5 mC. In various embodiments, each Y of SEQ ID NOS: 16 to 75 and SEQ ID NOS: 76 to 3485 is 5 mC. 
     In various embodiments, at least one Y of SEQ ID NOS: 16 to 75 and SEQ ID NOS: 76 to 3485 is C. In various embodiments, each Y of SEQ ID NOS: 16 to 75 and SEQ ID NOS: 76 to 3485 is C. 
     As used herein, the term “TEG,” “triethylene glycol tail,” or “EG3” refers to triethylene glycol moieties conjugated to the oligomer, e.g., at its 3′- or 5′-end. For example, in some embodiments, “TEG” includes wherein T of the compound of, for example, formulas (I), (IV), (V), (VI), (VII), and (VIII) is of the formula: 
     
       
         
         
             
             
         
       
     
     As used herein, the term a “therapeutically effective amount” or “effective amount” of a therapeutic agent or composition refers to an amount effective in the prevention or treatment of a disorder for the treatment of which the composition is effective. A “disorder” refers to any Duchenne muscular dystrophy or related disorder, including BMD, limb-girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy, myotonic muscular dystrophy, oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, muscle wasting conditions or disorders, such as AIDS, cancer or chemotherapy related muscle wasting, and fibrosis or fibrosis-related disorders (for example, skeletal muscle fibrosis). 
     As used herein, the terms “quantifying,” “quantification” or other related words refer to determining the quantity, mass, or concentration in a unit volume, of a nucleic acid, oligonucleotide, oligomer, peptide, polypeptide, or protein. 
     In various embodiments, as used herein, the term “treatment” includes treatment of a subject (e.g. a mammal, such as a human) or a cell to alter the current course of the subject or cell. Treatment includes, but is not limited to, administration of a pharmaceutical composition, and may be performed either prophylactically or subsequent to the initiation of a pathologic event or contact with an etiologic agent. Also included are “prophylactic” treatments, which can be directed to reducing the rate of progression of the disease or condition being treated, delaying the onset of that disease or condition, or reducing the severity of its onset. “Treatment” or “prophylaxis” does not necessarily indicate complete eradication, cure, or prevention of the disease or condition, or associated symptoms thereof. 
     II. MODULATION OF THE SPLICING OF A PRE-MRNA TRANSCRIPT 
     For illustration purposes, and without being bound by theory, where a therapeutic agent is a modified antisense oligomer, these are believed to facilitate blocking, inhibiting or modulating the processing of a pre-mRNA, such as by inhibiting the action of a spliceosome and production of a mature mRNA transcript, and may also induce degradation of targeted mRNAs. 
     In some instances, a spliceosome may be inhibited from binding to an exon/intron splice junction such that an exon/intron splice junction is skipped and one or more exons are removed from an mRNA transcript. A mature mRNA transcript having one or more exons less than a wildtype mRNA transcript may result in an mRNA transcript that maintains the open reading frame such that the mRNA transcript may be translated to functional protein rather than degraded. A protein translated from an mRNA transcript having fewer exons than the wildtype mRNA may result in a transcribed protein comprising fewer amino acid residues than a protein transcribed from a wildtype mRNA transcript. A functional protein composed of fewer amino acid residues than a wildtype protein may have the same or similar activity/functionality as the wildtype protein. The modified antisense oligomer may be said to be “directed to” or “targeted against” a target sequence or target region with which it hybridizes. In certain embodiments, the target sequence includes a region including a 3′ or 5′ splice junction site of a pre-mRNA, a branch point, Exonic Splicing Enhancers (ESE) or Intronic Splicing Enhancers (ISE), or other sequence involved in the regulation of splicing. Within an intron, a donor site (5′ end of the intron) and an acceptor site (3′ end of the intron) are required for splicing. The splice donor site includes an almost invariant sequence GUat the 5′ end of the intron, within a larger, less highly conserved region. The splice acceptor site at the 3′ end of the intron terminates the intron with an almost invariant AG sequence. The target sequence may include sequences entirely within an exon where no part of the target sequence spans a splice junction, within an exon/intron splice junction site, or spanning an exon/intron splice junction. The target sequence may include an exon/intron donor splice site. 
     A modified antisense oligomer having a sufficient sequence complementarity to a target pre-mRNA sequence to modulate splicing of the target RNA includes where the modified antisense oligomer has a sequence sufficient to trigger the masking or hindrance of a binding site for a spliceosome complex that would otherwise affect such splicing and/or otherwise includes alterations in the three-dimensional structure of the targeted pre-mRNA. 
     A. Modulation of the Splicing of Myostatin Pre-mRNA 
     Various aspects relate to methods for modulating the splicing of intron and exons of myostatin pre-mRNA. Further aspects relate to inhibiting splicing at the splice junction site of intron 1/exon 2 and exon 2/intron 2 of myostatin pre-mRNA. In further aspects, expression of myostatin exon 2 coding mRNA is inhibited, such as relative to exon-2 wildtype mRNA, in a given sample (e.g., serum, plasma, tissue, cellular etc.). Various methods include administering an antisense oligomer described herein containing a targeting sequence that is complementary to a target region within the myostatin pre-mRNA, where expression of myostatin exon 2 mRNA is inhibited relative to the expression of exon-2 wildtype (i.e. control) mRNA. 
     In various embodiments, the modified antisense oligomer targeting sequence has sufficient length and complementarity to a sequence within a target region of myostatin pre-mRNA. In various embodiments, targeting sequences within a modified antisense oligomer hybridize to a region of the target sequences entirely within exon 2 where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction of myostatin pre-mRNA, such as, for example, the +24/−01 or +18/−07 region of intron 2/exon 2 or the −01/+21, −01/+25, or −09/+15 region of exon 2/intron 2 of myostatin pre-mRNA. In some embodiments, the modified antisense oligomers may about 12 bases to about 40 bases, and include a small number of mismatches, as long as the targeting sequence is sufficiently complementary to effect splice modulation upon hybridization to the target sequence, and optionally forms with the pre-mRNA a heteroduplex having a Tm of 45° C. or greater. 
     In various embodiments, the degree of complementarity between the antisense targeting sequence and the target sequence is sufficient to form a stable duplex. The region of complementarity of the modified antisense oligomers with the target sequence may be as short as 12-15 bases but can be 12-20 bases or more, e.g., 12-40 bases, 12-30 bases, 12-25 bases, 12-22 bases, 15-25 bases, 15-22 bases, or 15-20 bases, including all integers in between these ranges. In certain embodiments, a minimum length of complementary bases may be required to achieve the requisite binding Tm, as discussed herein. 
     B. Modulation of the Splicing of Dystrophin Pre-mRNA 
     Various aspects relate to methods for modulating the splicing of intron and exons of dystrophin pre-mRNA. Further aspects relate to inhibiting splicing at the splice junction site of an intron/exon and exon/intron splice junction of dystrophin pre-mRNA. In further aspects, expression of a truncated form of dystrophin coding mRNA is enhanced, such as relative to full length wildtype dystrophin mRNA, in a given sample (e.g., serum, plasma, tissue, cellular etc.). Various methods include administering an antisense oligomer described herein containing a targeting sequence that is complementary to a target region within the dystrophin pre-mRNA, where expression of a truncated form of dystrophin mRNA is enhanced relative to the expression of full length wildtype (i.e. control) mRNA. 
     In various embodiments, an antisense oligomer binds to a target region within an exon of dystrophin pre-mRNA. In embodiments, an antisense oligomer binds to an exon selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. In embodiments, the target region is entirely within an exon of dystrophin pre-mRNA where no part of the targeting sequence spans a splice junction, or is a region spanning an intron/exon or exon/intron splice junction. In embodiments, one or more exons of dystrophin pre-mRNA have one or more genetic mutations. In embodiments, an antisense oligomer targets an exon having one or more genetic mutations such that the exon is spliced out of the pre-mRNA transcript during processing to mature mRNA resulting in a shortened or truncated form of dystrophin mRNA. 
     In various embodiments, the modified antisense oligomer targeting sequence has sufficient length and complementarity to a sequence within a target region of dystrophin pre-mRNA. In various embodiments, targeting sequences within a modified antisense oligomer hybridize to a region of the target sequences entirely within one or more exons where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction of dystrophin pre-mRNA. In some embodiments, the modified antisense oligomers may about 8 bases to about 50 bases, and include a small number of mismatches, as long as the targeting sequence is sufficiently complementary to effect splice modulation upon hybridization to the target sequence, and optionally forms with the RNA a heteroduplex having a Tm of 45° C. or greater. 
     In various embodiments, the degree of complementarity between the antisense targeting sequence and the target sequence is sufficient to form a stable duplex. The region of complementarity of the modified antisense oligomers with the target sequence may be as short as 8-15 bases but can be 8-20 bases or more, e.g., 8-40 bases, 8-30 bases, 8-25 bases, 8-22 bases, 8-25 bases, 8-22 bases, 8-20 bases. 17 to 20 bases, 17 to 22 bases, 17 bases to 25 bases, 17 to 30 bases, 17 to 40 bases, or 20 to 30 bases, including all integers in between these ranges. In certain embodiments, a minimum length of complementary bases may be required to achieve the requisite binding Tm, as discussed herein. 
     In various aspects, the oligomers are configured for additional functionality, including but not limited to bio-availability, stability, cellular update, and resistance to nuclease degradation. Generally, oligomers comprising 50 bases may be suitable, where at least a minimum number of bases, e.g., 8 or 12 bases, are complementary to the target sequence. In various aspects, the oligomers are configured to enhance facilitated or active cellular uptake. In various aspects, the modified antisense oligomers comprise one or more phosphoramidate morpholino monomer or phosphorodiamidate morpholino monomer subunits. In various embodiments, the modified antisense oligomers, comprise about 8-50 phosphoramidate morpholino monomer or phosphorodiamidate morpholino monomer subunits. In various embodiments, the modified antisense oligomers, comprise about 8-30 phosphoramidate morpholino monomer or phosphorodiamidate morpholino monomer subunits. In various embodiments, the modified antisense oligomers, comprise about 17-40 phosphoramidate morpholino monomer or phosphorodiamidate morpholino monomer subunits. In various embodiments, the modified antisense oligomers, comprise about 12-25 phosphoramidate morpholino monomer or phosphorodiamidate morpholino monomer subunits. In various embodiments, the modified antisense oligomers, comprise about 15-25 phosphoramidate morpholino monomer or phosphorodiamidate morpholino monomer subunits. In various embodiments, the modified antisense oligomers, comprise about 15-22 phosphoramidate morpholino monomer or phosphorodiamidate morpholino monomer subunits. 
     In various aspects, the modified antisense oligomers comprise, consist of, or consist essentially of 8 to 50 subunits, optionally comprising at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and a targeting sequence complementary to a target region of 10 or more contiguous nucleotides within a pre-mRNA. In various embodiments, the target region comprises 10, 12 or more contiguous nucleotides entirely within one or more exons where no part of the targeting sequence spans a splice junction, or within a region spanning an intron/exon or exon/intron splice junction of a myostatin or dystrophin gene. 
     In various embodiments, the target region of a myostatin pre-mRNA comprises a region within exon 2, intron 1/exon 2 or exon 2/intron 2 of myostatin pre-mRNA. In further embodiments, the target region comprises the +24/−01 or +18/−07 region of intron 2/exon 2 or the −01/+21,−01/+25, or −09/+15 region of exon 2/intron 2 of myostatin pre-mRNA. 
     In various embodiments, the target region of a dystrophin pre-mRNA comprises a region within one or more of an exon selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55 of dystrophin pre-mRNA. 
     In various aspects, the modified antisense oligomers comprise, consist of, or consist essentially of 10 to 50 subunits, optionally comprising at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and a targeting sequence comprising, consisting of, or consisting essentially of, a sequence selected from SEQ IDS 16 to 75 and SEQ ID NOS: 76-3485. Preferably, in some aspects, the modified antisense oligomer comprises a sequence selected from SEQ IDS 71-75 and SEQ ID NO: 76. 
     Additional aspects include modified antisense oligomers of 8 to 50 subunits that specifically hybridize to a target region within myostatin or dystrophin pre mRNA. 
     In various embodiments, the target region within myostatin pre-mRNA comprises a region within exon 2, intron 1/exon 2 or exon 2/intron 2 (or a region which spans a splice junction) of the myostatin gene. In various embodiments, the target region comprises a region entirely within exon 2 of myostatin pre-mRNA. In various embodiments, the target region comprises a region within intron 1/exon2 or exon 2/intron 2. In various embodiments, the target region comprises a region spanning an intron 1/exon2 or exon 2/intron 2 splice junction. In further embodiments, the target region comprises the +24/−01 or +18/−07 region of intron 2/exon 2 or the −01/+21, −01/+25, or −09/+15 region of exon 2/intron 2 of myostatin pre-mRNA. 
     Additional aspects include modified antisense oligomers having a nucleotide analog subunit comprising a modified sugar moiety. In various embodiments, the modified sugar moiety is selected from a peptide nucleic acid (PNA) subunit, a locked nucleic acid (LNA) subunit, a 2′O,4′C-ethylene-bridged nucleic acid (ENA) subunit, a tricyclo-DNA (tc-DNA) subunit, a 2′ O-methyl subunit, a 2′ O-methoxyethyl subunit, a 2′-fluoro subunit, a 2′-O-[2-(N-methylcarbamoyl)ethyl]subunit, and a morpholino subunit. 
     Additional aspects include modified antisense oligomers having a nucleotide analog subunit comprising a modified internucleoside linkage. In various embodiments, the modified intemucleoside linkage is selected from a phosphorothioate internucleoside linkage, a phosphoramidate internucleoside linkage, a phosphorodiamidate intemucleoside linkage, and a phosphorotriamidate internucleoside linkage. In further embodiments, the phosphorodiamidate intemucleoside linkage comprises a phosphorous atom that is covalently bonded to a (1,4-piperazin)-1-yl moiety, a substituted (1,4-piperazin)-1-yl moiety, a 4-aminopiperidin-1-yl moiety, or a substituted 4-aminopiperidin-1-yl moiety. 
     Additional aspects include modified antisense oligomers having a nucleotide analog subunit comprising at least one combination of a modified sugar moiety and a modified intemucleoside linkage, wherein various embodiments, one or more subunits are selected from: 
     a morpholino subunit optionally substituted with a phosphoramidate internucleoside linkage, a phosphorodiamidate internucleoside linkage, phosphorotriamidate intemucleoside linkage, or a phosphorothioate intemucleoside linkage,
         a 2′ O-methyl subunit optionally substituted with a phosphoramidate intemucleoside linkage, a phosphorodiamidate internucleoside linkage, or a phosphorothioate intemucleoside linkage,   a 2′O-methoxyethyl subunit optionally substituted with a phosphoramidate intemucleoside linkage, a phosphorodiamidate internucleoside linkage, or a phosphorothioate intemucleoside linkage,   a 2′-fluoro subunit optionally substituted with a phosphoramidate internucleoside linkage, a phosphorodiamidate internucleoside linkage, or a phosphorothioate internucleoside linkages,   a 2′O,4′C-ethylene-bridged nucleic acid subunit optionally substituted with a phosphoramidate internucleoside linkage, a phosphorodiamidate internucleoside linkage, or a phosphorothioate internucleoside linkage,   a 2′-O-[2-(N-methylcarbamoyl)ethyl]subunit optionally substituted with a phosphoramidate internucleoside linkage, a phosphorodiamidate internucleoside linkage, or a phosphorothioate internucleoside linkage,   a tricyclo-DNA subunit optionally substituted with a phosphoramidate internucleoside linkage, a phosphorodiamidate internucleoside linkage, or a phosphorothioate internucleoside linkage,   a locked nucleic acid subunit optionally substituted with a phosphoramidate internucleoside linkage, a phosphorodiamidate internucleoside linkage, or a phosphorothioate internucleoside linkage,   a morpholino subunit further comprising a phosphorodiamidate internucleoside linkage where a phosphorous atom of the phosphorodiamidate is covalently bonded to the nitrogen atom of the morpholino ring, and is covalently bonded to a (1,4-piperazin)-1-yl moiety or to a substituted (1,4-piperazin)-1-yl moiety,   a morpholino subunit further comprising a phosphorodiamidate internucleoside linkage where a phosphorus atom of the phosphorodiamidate is covalently bonded to a 4-aminopiperdin-1-yl moiety or a substituted 4-aminopiperdin-1-yl moiety,   a morpholino subunit further comprising a phosphorodiamidate internucleoside linkage where a phosphorus atom of the phosphorodiamidate is covalently bonded to the nitrogen atom of the morpholino ring, and is covalently bonded to a dimethylamino moiety,   a ribose sugar subunit substituted with a phosphorothioate internucleoside or a phosphoramidate internucleoside linkage,   a deoxyribose sugar subunit substituted with a phosphorothioate internucleoside linkage or a phosphoramidate internucleoside linkage,   a peptide nucleic acid subunit optionally substituted,       

     or any combination of the foregoing. 
     In various aspects and embodiments, modified antisense oligomers of the disclosure further comprise a peptide covalently bonded to the modified antisense oligomer. In various embodiments, an arginine-rich cell-penetrating peptide is conjugated to the 3′ or the 5′ end of the modified antisense oligomer. 
     In various embodiments, a modified antisense oligomer may consist of about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 bases, or range from 8 to 50, 8 to 40, 8 to 30, 8 to 25, 8 to 20, 8 to 18, 12 to 30, 12 to 25, 10 to 20, 10 to 18, 15 to 30, 15 to 25, 15 to 20, 15 to 18, 17 to 20, 17 to 30, 17 to 40, 18 to 30, 18 to 25, or 18 to 20 bases, including all integers in between these ranges. In some embodiments, the modified antisense oligomer is about 8 to about 50, about 8 to about 40 or about 8 to about 30 bases in length. In some embodiments, the modified antisense oligomer is about 12 to about 25 bases in length. In some embodiments, a modified antisense oligomer sequence comprises at least about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 contiguous or non-contiguous bases that are complementary to a target sequence within myostatin or dystrophin pre-mRNA, such as, exon 2, intron 1/exon 2 or exon 2/intron 2 of myostatin pre-mRNA, or one or more of exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55 of dystrophin pre-mRNA, or sequences that span at least a portion of myostatin or dystrophin pre-mRNA. 
     A modified antisense oligomer may typically comprise a base sequence which is sufficiently complementary to a sequence or region within exon 2, intron 1/exon 2 or exon 2/intron 2 of the myostatin pre-mRNA sequence of the myostatin protein. Table 1 below recites sequences or regions within exon 2, intron 1/exon 2 and exon 2/intron 2. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Exemplary Sequences of exon 2, intron 1/exon 2 and exon 2/intron 2 of the 
               
               
                 Myostatin Gene 
               
            
           
           
               
               
            
               
                 Region Within 
                   
               
               
                 Myostatin Gene 
                 Sequence 
               
               
                   
               
               
                 Intron 1/exon 2/intron 2 
                 agcaacttttcttttcttattcatttatag/ctgattttctaatgcaagtggatggaaaaccca 
               
               
                 (SEQ ID NO: 1) 
                 aatgttgcttctttaaatttagctctaaaatacaatacaataaagtagtaaaggcccaact 
               
               
                   
                 atggatatatttgagacccgtcgagactcctacaacagtgtttgtgcaaatcctgagact 
               
               
                   
                 catcaaacctatgaaagacggtacaaggtatactggaatccgatctctgaaacttgaca 
               
               
                   
                 tgaacccaggcactggtatttggcagagcattgatgtgaagacagtgttgcaaaattg 
               
               
                   
                 gctcaaacaacctgaatccaacttaggcattgaaataaaagctttagatgagaatggtc 
               
               
                   
                 atgatcttgctgtaaccttcccaggaccaggagaagatgggctg/gtaagtgataactg 
               
               
                   
                 aaaataacattataat 
               
               
                   
               
               
                 SA2 intron 1/exon 2 
                 cttttcttttcttattcatttatag/ctgattttctaatgcaagtggatgg 
               
               
                 (SEQ ID NO: 2) 
               
               
                   
               
               
                 SD2 exon 2/intron 2 
                 accttcccaggaccaggagaagatgggctg/gtaagtgataactgaaaataacattat 
               
               
                 (SEQ ID NO: 3) 
                 aat 
               
               
                   
               
               
                   
               
               
                 “/” indicates the splice site 
               
            
           
         
       
     
     A modified antisense oligomer may typically comprise a base sequence which is sufficiently complementary to a sequence or region within one or more of exons exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55 of dystrophin pre-mRNA sequence of the dystrophin protein. Table 2 below recites sequences or regions within exons exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, and exon 55. 
     
       
         
           
               
             
               
                 TABLE 2 
               
             
            
               
                   
               
               
                 Exemplary Sequences of Exon 7, Exon 8, Exon 9, Exon 19, Exon 23, Exon 
               
               
                 44, Exon 45, Exon 50, Exon 51, Exon 52, Exon 53, or Exon 55 of the Dystrophin Gene. 
               
            
           
           
               
               
            
               
                 Region Within 
                   
               
               
                 Dystrophin Gene 
                 Sequence 
               
               
                   
               
               
                 Exon 7 (SEQ ID NO: 4) 
                 gccagacctatttgactggaatagtgtggtttgccagcagtcagccacacaacgactg 
               
               
                   
                 gaacatgcattcaacatcgccagatatcaattaggcatagagaaactactcgatcctg 
               
               
                   
                 aag 
               
               
                   
               
               
                 Exon 8 (SEQ ID NO: 5) 
                 atgttgataccacctatccagataagaagtccatcttaatgtacatcacatcactcttcca 
               
               
                   
                 agttttgcctcaacaagtgagcattgaagccatccaggaagtggaaatgttgccaagg 
               
               
                   
                 ccacctaaagtgactaaagaagaacattttcagttacatcatcaaatgcactattctcaa 
               
               
                   
                 cag 
               
               
                   
               
               
                 Exon 9 (SEQ ID NO: 6) 
                 atcacggtcagtctagcacagggatatgagagaacttcttcccctaagcctcgattcaa 
               
               
                   
                 gagctatgcctacacacaggctgcttatgtcaccacctctgaccctacacggagccca 
               
               
                   
                 tttccttcacag 
               
               
                   
               
               
                 Exon 19 (SEQ ID NO: 7) 
                 gccatagagcgagaaaaagctgagaagttcagaaaactgcaagatgccagcagatc 
               
               
                   
                 agctcaggccctggtggaacagatggtgaatg 
               
               
                   
               
               
                 Exon 23 (SEQ ID NO: 8) 
                 gctttacaaagttctctgcaagagcaacaaagtggcctatactatctcagcaccactgt 
               
               
                   
                 gaaagagatgtcgaagaaagcgccctctgaaattagccggaaatatcaatcagaattt 
               
               
                   
                 gaagaaattgagggacgctggaagaagctctcctcccagctggttgagcattgtcaa 
               
               
                   
                 aagctagaggagcaaatgaataaactccgaaaaattcag 
               
               
                   
               
               
                 Exon 44 (SEQ ID NO: 9) 
                 gcgatttgacagatctgttgagaaatggcggcgttttcattatgatataaagatatttaat 
               
               
                   
                 cagtggctaacagaagctgaacagtttctcagaaagacacaaattcctgagaattggg 
               
               
                   
                 aacatgctaaatacaaatggtatcttaag 
               
               
                   
               
               
                 Exon 45 (SEQ ID NO: 
                 gaactccaggatggcattgggcagcggcaaactgttgtcagaacattgaatgcaact 
               
               
                 10) 
                 ggggaagaaataattcagcaatcctcaaaaacagatgccagtattctacaggaaaaat 
               
               
                   
                 tgggaagcctgaatctgcggtggcaggaggtctgcaaacagctgtcagacagaaaa 
               
               
                   
                 aagag 
               
               
                   
               
               
                 Exon 50 (SEQ ID NO: 
                 aggaagttagaagatctgagctctgagtggaaggcggtaaaccgtttacttcaagag 
               
               
                 11) 
                 ctgagggcaaagcagcctgacctagctcctggactgaccactattggagcct 
               
               
                   
               
               
                 Exon 51 (SEQ ID NO: 
                 ctcctactcagactgttactctggtgacacaacctgtggttactaaggaaactgccatct 
               
               
                 12) 
                 ccaaactagaaatgccatcttccttgatgttggaggtacctgctctggcagatttcaacc 
               
               
                   
                 gggcttggacagaacttaccgactggctttctctgcttgatcaagttataaaatcacaga 
               
               
                   
                 gggtgatggtgggtgaccttgaggatatcaacgagatgatcatcaagcagaag 
               
               
                   
               
               
                 Exon 52 (SEQ ID NO: 
                 gcaacaatgcaggatttggaacagaggcgtccccagttggaagaactcattaccgct 
               
               
                 13) 
                 gcccaaaatttgaaaaacaagaccagcaatcaagaggctagaacaatcattacggat 
               
               
                   
                 cgaa 
               
               
                   
               
               
                 Exon 53 (SEQ ID NO: 
                 ttgaaagaattcagaatcagtgggatgaagtacaagaacaccttcagaaccggaggc 
               
               
                 14) 
                 aacagttgaatgaaatgttaaaggattcaacacaatggctggaagctaaggaagaag 
               
               
                   
                 ctgagcaggtcttaggacaggccagagccaagcttgagtcatggaaggagggtccc 
               
               
                   
                 tatacagtagatgcaatccaaaagaaaatcacagaaaccaag 
               
               
                   
               
               
                 Exon 55 (SEQ ID NO: 
                 ggtgagtgagcgagaggctgctttggaagaaactcatagattactgcaacagttcccc 
               
               
                 15) 
                 ctggacctggaaaagtttcttgcctggcttacagaagctgaaacaactgccaatgtcct 
               
               
                   
                 acaggatgctacccgtaaggaaaggctcctagaagactccaagggagtaaaagag 
               
               
                   
                 ctgatgaaacaatggcaa 
               
               
                   
               
            
           
         
       
     
     Preferably, a modified antisense oligomer effectively decreases expression of an exon, such as exon 2, thereby decreasing expression of a functional myostatin protein. Preferably, a modified dystrophin antisense oligomer effectively modulates abberant splicing of the dystrophin pre-mRNA, thereby increasing expression of a functional or semi-functional dystrophin protein. This requirement is optionally met when the oligomer compound has the ability to be actively taken up by mammalian cells, and once taken up, form a stable duplex (or heteroduplex) with the target mRNA, optionally with a Tm greater than about 40° C. or 45° C. 
     “Complementary” or “complementary” as used herein, refers to a targeting sequence of a modified antisense oligomer having about 90% to about 100% of the nucleotide targeting sequence complementary to a target sequence. In embodiments, a complementary nucleotide targeting sequence specifically hybridizes to a target sequence to induce a desired effect, for example, a therapeutic effect as described herein. In certain embodiments, targeting sequences of modified antisense oligomers may be 100% complementary to the target sequence, or may include mismatches, e.g., to accommodate variants, as long as a heteroduplex formed between the oligomer targeting sequence and target sequence is sufficiently stable to withstand the action of cellular nucleases and other modes of degradation which may occur in vivo. Hence, certain oligomer targeting sequences may have substantial complementarity, meaning, about or at least about 90% sequence complementarity, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence complementarity, between the oligomer targeting sequence and the target sequence. Oligomer internucleoside linkages that are less susceptible to cleavage by nucleases are provided herein. Mismatches, if present, are typically less destabilizing toward the end regions of the hybrid duplex than in the middle. The number of mismatches allowed will depend on the length of the oligomer, the percentage of G:C base pairs in the duplex, and the position of the mismatch(es) in the duplex, according to well understood principles of duplex stability. Although such a modified antisense oligomer need not necessarily comprise 100% complementary to the target sequence, it should have sufficient complementarity to effectively, stably and specifically bind to the target sequence, such that splicing of the target pre-mRNA is sufficiently modulated, for example, to achieve a therapeutic effect, as described herein. 
     Without being bound by theory, the stability of the duplex formed between an oligomer and a target sequence is believed to be a function of the binding Tm and the susceptibility of the duplex to cellular enzymatic cleavage. The Tm of an oligomer with respect to a complementary-sequence RNA duplex may be measured by conventional methods, such as those described by Hames et al., Nucleic Acid Hybridization, IRL Press, 1985, pp. 107-108 or as described in Miyada C. G. and Wallace R. B., 1987, Oligomer Hybridization Techniques, Methods Enzymol. Vol. 154 pp. 94-107, the contents of which are incorporated herein by reference. In various embodiments, the modified antisense oligomers have a binding Tm, with respect to a complementary-sequence RNA duplex, of greater than body temperature, such as, for example, greater than about 45° C. or 50° C. Tm&#39;s in the range 60-80° C. or greater are also included. According to well-known principles, the Tm of an oligomer, with respect to a complementary-based RNA hybrid duplex, can be increased by increasing the ratio of C:G paired bases in the duplex, and/or by increasing the length (in base pairs) of the heteroduplex. 
     Table 3 below shows exemplary targeting sequences (in a 5′-to-3′ orientation) that are complementary to the target regions within exon 2, intron 1/exon 2 or exon 2/intron 2 of myostatin pre-mRNA. 
     
       
         
           
               
               
             
               
                   
               
               
                 Targeting Sequence 
                 Sequence 
               
               
                   
               
             
            
               
                 MSTN-D30 
                 cagcccatcttctcctggtcctgggaag 
               
               
                 (SEQ ID NO: 16) 
                 gt 
               
               
                   
               
               
                 muhuMSTN-SD2(+24−01) 
                 ccagcccatcttctcctggtcctgg 
               
               
                 (SEQ ID NO: 17) 
               
               
                   
               
               
                 muhuMSTN-SD2(+18−07) 
                 cacttaccagcccatcttctcctgg 
               
               
                 (SEQ ID NO: 18) 
               
               
                   
               
               
                 huMSTN-SA2(−01+25) 
                 ccatccgcttgcattagaaagtcagc 
               
               
                 (SEQ ID NO: 19) 
               
               
                   
               
               
                 huMSTN-SA2(−09+15) 
                 gcattagaaaatcagctataaatg 
               
               
                 (SEQ ID NO: 20) 
               
               
                   
               
               
                 huMSTN-SA2(−01+21) 
                 ccacttgcattagaaaatcagc 
               
               
                 (SEQ ID NO: 21) 
               
               
                   
               
               
                 huMSTN-SA2(−07+18) 
                 cttgcattagaaaatcagctataaa 
               
               
                 (SEQ ID NO: 22) 
               
               
                   
               
               
                 huMSTN-SA2(−05+20) 
                 cacttgcattagaaaatcagctata 
               
               
                 (SEQ ID NO: 23) 
               
               
                   
               
               
                 huMSTN-SA2(−04+21) 
                 ccacttgcattagaaaatcagctat 
               
               
                 (SEQ ID NO: 24) 
               
               
                   
               
               
                 huMSTN-SA2(−03+22) 
                 tccacttgcattagaaaatcagcta 
               
               
                 (SEQ ID NO: 25) 
               
               
                   
               
               
                 huMSTN-SA2(−02+23) 
                 atccacttgcattagaaaatcagct 
               
               
                 (SEQ ID NO: 26) 
               
               
                   
               
               
                 huMSTN-SA2(−01+24) 
                 catccacttgcattagaaaatcagc 
               
               
                 (SEQ ID NO: 27) 
               
               
                   
               
               
                 muhuMSTN-SD2(+04−21) 
                 ttattttcagttatcacttaccagc 
               
               
                 (SEQ ID NO: 28) 
               
               
                   
               
               
                 muhuMSTN-SD2(+07−18) 
                 ttttcagttatcacttaccagccca 
               
               
                 (SEQ ID NO: 29) 
               
               
                   
               
               
                 muhuMSTN-SD2(+10−15) 
                 tcagttatcacttaccagcccatct 
               
               
                 (SEQ ID NO: 30) 
               
               
                   
               
               
                 muhuMSTN-SD2(+13−12) 
                 gttatcacttaccagcccatcttct 
               
               
                 (SEQ ID NO: 31) 
               
               
                   
               
               
                 muhuMSTN-SD2(+16−09) 
                 atcacttaccagcccatcttctcct 
               
               
                 (SEQ ID NO: 32) 
               
               
                   
               
               
                 muhuMSTN-SD2(+19−06) 
                 acttaccagcccatcttctcctggt 
               
               
                 (SEQ ID NO: 33) 
               
               
                   
               
               
                 muhuMSTN-SD2(+22−03) 
                 taccagcccatcttctcctggtcct 
               
               
                 (SEQ ID NO: 34) 
               
               
                   
               
               
                 muhuMSTN-SD2(+01−24) 
                 atgttattttcagttatcacttacc 
               
               
                 (SEQ ID NO: 35) 
               
               
                   
               
               
                 muhuMSTN-SD2(+02−23) 
                 tgttattttcagttatcacttacca 
               
               
                 (SEQ ID NO: 36) 
               
               
                   
               
               
                 muhuMSTN-SD2(+03−22) 
                 gttattttcagttatcacttaccag 
               
               
                 (SEQ ID NO: 37) 
               
               
                   
               
               
                 muhuMSTN-SD2(+05−20) 
                 tattttcagttatcacttaccagcc 
               
               
                 (SEQ ID NO: 38) 
               
               
                   
               
               
                 muhuMSTN-SD2(+06−19) 
                 attttcagttatcacttaccagccc 
               
               
                 (SEQ ID NO: 39) 
               
               
                   
               
               
                 muhuMSTN-SD2(+08−17) 
                 tttcagttatcacttaccagcccat 
               
               
                 (SEQ ID NO: 40) 
               
               
                   
               
               
                 muhuMSTN-SD2(+09−16) 
                 ttcagttatcacttaccagcccatc 
               
               
                 (SEQ ID NO: 41) 
               
               
                   
               
               
                 muhuMSTN-SD2(+11−14) 
                 cagttatcacttaccagcccatctt 
               
               
                 (SEQ ID NO: 42) 
               
               
                   
               
               
                 muhuMSTN-SD2(+12−13) 
                 agttatcacttaccagcccatcttc 
               
               
                 (SEQ ID NO: 43) 
               
               
                   
               
               
                 Mstn D (′139 app) 
                 cagcccatcttctcctggtcctgggaag 
               
               
                 (SEQ ID NO: 44) 
                 gt 
               
               
                   
               
               
                 GDF8/D3 (′139 app) 
                 cagcccatcttctcctggtc 
               
               
                 (SEQ ID NO: 45) 
               
               
                   
               
               
                 GDF8/D2 (′139 app) 
                 tctcctggtcctgggaaggt 
               
               
                 (SEQ ID NO: 46) 
               
               
                   
               
               
                 GDF8/D1 (′139 app) 
                 ctgggaaggttacagcaaga 
               
               
                 (SEQ ID NO: 47) 
               
               
                   
               
               
                 huMSTN-SD2(+18+1) 
                 cagcccatcttctcctgg 
               
               
                 (SEQ ID NO: 48) 
               
               
                   
               
               
                 muhuMSTN-SD2(+25+03) 
                 gcccatcttctcctggtcctggg 
               
               
                 (SEQ ID NO: 49) 
               
               
                   
               
               
                 huMSTN-SA2(+26+50) 
                 tttaaagaagcaacatttgggtttt 
               
               
                 (SEQ ID NO: 50) 
               
               
                   
               
               
                 huMSTN-SA2(+41+65) 
                 tattttagagctaaatttaaagaag 
               
               
                 (SEQ ID NO: 51) 
               
               
                   
               
               
                 huMSTN-SA2(+56+80) 
                 tactttattgtattgtattttagag 
               
               
                 (SEQ ID NO: 52) 
               
               
                   
               
               
                 huMSTN-SA2(+71+95) 
                 tagttgggcctttactactttattg 
               
               
                 (SEQ ID NO: 53) 
               
               
                   
               
               
                 huMSTN-SA2(+86+110) 
                 tctcaaatatatccatagttgggcc 
               
               
                 (SEQ ID NO: 54) 
               
               
                   
               
               
                 huMSTN-SA2(+91+115) 
                 acgggtctcaaatatatccatagtt 
               
               
                 (SEQ ID NO: 55) 
               
               
                   
               
               
                 huMSTN-SA2(+101+130) 
                 gttgtaggagtctcgacgggtctcaaat 
               
               
                 (SEQ ID NO: 56) 
                 at 
               
               
                   
               
               
                 huMSTN-SA2(+111+135) 
                 acactgttgtaggagtctcgacggg 
               
               
                 (SEQ ID NO: 57) 
               
               
                   
               
               
                 huMSTN-SA2(+141+165) 
                 taggtttgatgagtctcaggatttg 
               
               
                 (SEQ ID NO: 58) 
               
               
                   
               
               
                 huMSTN-SA2(+151+175) 
                 ccgtctttcataggtttgatgagtc 
               
               
                 (SEQ ID NO: 59) 
               
               
                   
               
               
                 huMSTN-SA2(+160+189) 
                 cagtataccttgtaccgtctttcatagg 
               
               
                 (SEQ ID NO: 60) 
                 tt 
               
               
                   
               
               
                 huMSTN-SA2(+196+220) 
                 gggttcatgtcaagtttcagagatc 
               
               
                 (SEQ ID NO: 61) 
               
               
                   
               
               
                 huMSTN-SA2(+204+233) 
                 aataccagtgcctgggttcatgtcaagt 
               
               
                 (SEQ ID NO: 62) 
                 tt 
               
               
                   
               
               
                 huMSTN-SA2(+210+234) 
                 aaataccagtgcctgggttcatgtc 
               
               
                 (SEQ ID NO: 63) 
               
               
                   
               
               
                 huMSTN-SA2(+216+240) 
                 tctgccaaataccagtgcctgggtt 
               
               
                 (SEQ ID NO: 64) 
               
               
                   
               
               
                 huMSTN-SA2(+231+255) 
                 tcttcacatcaatgctctgccaaat 
               
               
                 (SEQ ID NO: 65) 
               
               
                   
               
               
                 huMSTN-SA2(+261+285) 
                 caggttgtttgagccaattttgcaa 
               
               
                 (SEQ ID NO: 66) 
               
               
                   
               
               
                 huMSTN-SA2(+276+291) 
                 tgcctaagttggattcaggttgttt 
               
               
                 (SEQ ID NO: 67) 
               
               
                   
               
               
                 huMSTN-SA2(+291+305) 
                 aagcttttatttcaatgcctaagtt 
               
               
                 (SEQ ID NO: 68) 
               
               
                   
               
               
                 huMSTN-SA2(+306+330) 
                 gaccattctcatctaaagcttttat 
               
               
                 (SEQ ID NO: 69) 
               
               
                   
               
               
                 huMSTN-SA2(+321+345) 
                 ttacagcaagatcatgaccattctc 
               
               
                 (SEQ ID NO: 70) 
               
               
                   
               
               
                 “/” indicates the splice site 
               
            
           
         
       
     
     Certain modified antisense oligomers thus comprise, consist, or consist essentially of a sequence in Table 3 (e.g., SEQ ID NOS: 16 to 75), is selected from SEQ ID NOS: 16 to 75, is a fragment of at least 12 contiguous nucleotides of a sequence selected from SEQ ID NOS: 16 to 75, or is a variant having at least 90% sequence identity to a sequence selected from SEQ ID NOS: 16 to 75, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). For instance, certain modified antisense oligomers comprise about or at least about 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 contiguous or non-contiguous nucleotides of any of SEQ ID NOS: 16 to 75. For non-contiguous portions, intervening nucleotides can be deleted or substituted with a different nucleotide, or intervening nucleotides can be added. Additional examples of variants include oligomers having about or at least about 90% sequence identity or homology, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity or homology, over the entire length of any of SEQ ID NOS: 16 to 75. In certain embodiments, the targeting sequence is selected from SEQ ID NOS: 16 to 75. 
     Oligonucleotides that target the dystrophin gene are disclosed in WO 2006/000057, WO 2011/057350, WO 2010/048586, WO 2014/100714, WO 2014/153220, US Application No. US20140315862, US Application No. US20140323544, US Application No. US20120202752, US Application No. US20030235845, US Application No. US20110312086, US Application No. US20090312532, US Application No. US20090269755, US Application No. US20130211062, US Application No. US20140343266, US Application No. US20120059042, US Application No. US20110294753, US Application No. US20140113955, US Application No. US20150166996, US Application No. US20150203849, US Application No. US20150045413, and US Application No. US20140057964, which are hereby incorporated by reference in their entireties. 
     Certain modified antisense oligomers thus comprise, consist, or consist essentially of a sequence in Table 4 (e.g., SEQ ID NOS: 76 to 3485), is selected from SEQ ID NOS: 76 to 3485, is a fragment of at least 10 contiguous nucleotides of a sequence selected from SEQ ID NOS: 76 to 3485, or is a variant having at least 90% sequence identity to a sequence selected from SEQ ID NOS: 76 to 3485, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). For instance, certain modified antisense oligomers comprise about or at least about 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 contiguous or non-contiguous nucleotides of any of SEQ ID NOS: 76 to 3485. For non-contiguous portions, intervening nucleotides can be deleted or substituted with a different nucleotide, or intervening nucleotides can be added. Additional examples of variants include oligomers having about or at least about 90% sequence identity or homology, e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity or homology, over the entire length of any of SEQ ID NOS: 76 to 3485. In certain embodiments, the targeting sequence is selected from SEQ ID NOS: 76 to 3485. In some embodiments, a targeting sequence may comprise SEQ ID NO: 76. 
     The activity/functionality of modified antisense oligomers and variants thereof can be assayed according to routine techniques in the art. For example, splice forms and expression levels of surveyed RNAs may be assessed by any of a wide variety of well-known methods for detecting splice forms and/or expression of a transcribed nucleic acid or protein. Non-limiting examples of such methods include RT-PCR of spliced forms of RNA followed by size separation of PCR products, nucleic acid hybridization methods e.g., Northern blots and/or use of nucleic acid arrays; nucleic acid amplification methods; immunological methods for detection of proteins; protein purification methods; and protein function or activity assays. 
     RNA expression levels can be assessed by preparing mRNA/cDNA (i.e., a transcribed oligonucleotide) from a cell, tissue or organism, and by hybridizing the mRNA/cDNA with a reference oligonucleotide that is a complement of the assayed nucleic acid, or a fragment thereof cDNA can, optionally, be amplified using any of a variety of polymerase chain reaction or in vitro transcription methods prior to hybridization with the complementary oligonucleotide; preferably, it is not amplified. Expression of one or more transcripts can also be detected using quantitative PCR to assess the level of expression of the transcript(s). 
     III. MODIFIED ANTISENSE OLIGOMER CHEMISTRIES 
     A. General Characteristics 
     In various aspects and embodiments, the modified antisense oligomers specifically hybridize to target region within myostatin pre-mRNA. Exemplary modified antisense oligomers comprise a targeting sequence set forth in Table 3, a fragment of at least 12 contiguous nucleotides of a targeting sequence in Table 3, or a variant having at least 90% sequence identity to a targeting sequence in Table 3. Other exemplary modified antisense oligomers consist or consist essentially of a targeting sequence set forth in Table 3. 
     In various aspects and embodiments, the modified antisense oligomers specifically hybridize to target region within dystrophin pre-mRNA. Exemplary modified antisense oligomers comprise a targeting sequence set forth in Table 4, a fragment of at least 10 contiguous nucleotides of a targeting sequence in Table 4, or a variant having at least 90% sequence identity to a targeting sequence in Table 4. Other exemplary modified antisense oligomers consist or consist essentially of a targeting sequence set forth in Table 4. 
     Nuclease-resistant modified antisense oligomers are provided in a further aspect. In various embodiments, a modified antisense oligomer is provided comprising one or more intemucleoside linkage modification(s). In other embodiments, a modified antisense oligomer is provided comprising one or more modified sugar moieties. In other embodiments, a modified antisense oligomer is provided comprising a combination of one or more modified intemucleoside linkages and one or more modified sugar moieties. In other embodiments, a modified antisense oligomer is provided comprising a modified nucleobase, alone or in combination with any of a modified internucleoside linkage or a modified sugar moiety. 
     In various embodiments, a modified antisense oligomer may comprise an oligomer having completely modified internucleoside linkages, for example, 100% of the internucleoside linkages are modified (for example, a 25-mer modified antisense oligomer comprises 24 internucleoside linkages modified with one or any combination of the modifications as described herein). In various embodiments, a modified antisense oligomer may comprise about 100% to 2.5% of its internucleoside linkages modified. In various embodiments, a modified antisense oligomer may comprise about 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 2.5% of its internucleoside linkages modified, and iterations in between. In other embodiments, a modified antisense oligomer may comprise any combination of modifications as described herein. 
     In various embodiments, including embodiments in combination with embodiments of percent of modified internucleoside linkages, a modified antisense oligomer may comprise an oligomer having completely modified sugar moieties, for example, 100% of the sugar moieties are modified (for example, a 25 mer modified antisense oligomer comprises 25 sugar moieties modified with one or any combination of the modifications as described herein). In various embodiments, a modified antisense oligomer may comprise about 100% to 2.5% of its sugar moieties modified. In various embodiments, a modified antisense oligomer may comprise about 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, or 2.5% of its sugar moieties modified, and iterations in between. In other embodiments, a modified antisense oligomer may comprise any combination of modifications as described herein. 
     In various embodiments, the modified antisense oligomer is substantially uncharged, and is optionally suitable as a substrate for active or facilitated transport across the cell membrane. In some embodiments, all of the internucleoside linkages are uncharged. The ability of the oligomer to form a stable duplex with the target pre-mRNA may also relate to other features of the oligomer, including the length and degree of complementarity of the modified antisense oligomer with respect to the target, the ratio of G:C to A:T base matches, and the positions of any mismatched bases. The ability of the modified antisense oligomer to resist cellular nucleases may promote survival and ultimate delivery of the agent to the cell cytoplasm. 
     In various embodiments, the modified antisense oligomer has at least one internucleoside linkage that is positively charged or cationic at physiological pH. In further embodiments, the modified antisense oligomer has at least one internucleoside linkage that exhibits a pKa between about 5.5 and about 12. In further embodiments, the modified antisense oligomer contains about, at least about, or no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 internucleoside linkages that exhibits a pKa between about 4.5 and about 12. In some embodiments, the modified antisense oligomer contains about or at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% internucleoside linkages that exhibit a pKa between about 4.5 and about 12. Optionally, the modified antisense oligomer has at least one internucleoside linkage with both a basic nitrogen and an alkyl, aryl, or aralkyl group. In particular embodiments, the cationic internucleoside linkage or linkages comprise a 4-aminopiperdin-1-yl (APN) group, or a derivative thereof. In some embodiments, the modified antisense oligomer comprises a morpholino ring. While not being bound by theory, it is believed that the presence of a cationic linkage or linkages (e.g., APN group or APN derivative) in the oligomer facilitates binding to the negatively charged phosphates in the target nucleotide. Thus, the formation of a heteroduplex between mutant RNA and the cationic linkage-containing oligomer may be held together by both an ionic attractive force and Watson-Crick base pairing. 
     In various embodiments, the number of cationic linkages is at least 2 and no more than about half the total internucleoside linkages, e.g., about or no more than about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 cationic linkages. In some embodiments, however, up to all of the internucleoside linkages are cationic linkages, e.g., about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40 of the total internucleoside linkages are cationic linkages. In further embodiments, an oligomer of about 19-20 monomer subunits may have 2-10, e.g., 4-8, cationic linkages, and the remainder uncharged linkages. In other specific embodiments, an oligomer of 14-15 subunits may have 2-7, e.g., 2, 3, 4, 5, 6, or 7 cationic linkages and the remainder uncharged linkages. The total number of cationic linkages in the oligomer can thus vary from about 1 to 10 to 18 to 20 to 30 or more (including all integers in between), and can be interspersed throughout the oligomer. 
     In some embodiments, a modified antisense oligomer may have about or up to about 1 cationic linkage per every 2-5 or 2, 3, 4, or 5 uncharged linkages, such as about 4-5 or 4 or 5 per every 10 uncharged linkages. 
     Certain embodiments include modified antisense oligomers that contain about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% cationic linkages. In certain embodiments, optimal improvement in antisense activity may be seen if about 25% of the internucleoside linkages are cationic. In certain embodiments, enhancement may be seen with a small number e.g., 10-20% cationic linkages, or where the number of cationic linkages is in the range 50-80%, such as about 60%. 
     In further embodiments, the cationic linkages are interspersed along the internucleoside linkage. Such oligomers optionally contain at least two consecutive uncharged linkages; that is, the oligomer optionally does not have a strictly alternating pattern along its entire length. In specific instances, each one or two cationic linkage(s) is/are separated along the internucleoside linkage by at least 1, 2, 3, 4, or 5 uncharged linkages. 
     Also included are oligomers having blocks of cationic linkages and blocks of uncharged linkages. For example, a central block of uncharged linkages may be flanked by blocks of cationic linkages, or vice versa. In some embodiments, the oligomer has approximately equal-length 5′, 3′ and center regions, and the percentage of cationic linkages in the center region is greater than about 50%, 60%, 70%, or 80% of the total number of cationic linkages. 
     In certain modified antisense oligomers, the bulk of the cationic linkages (e.g., 70, 75%, 80%, 90% of the cationic linkages) are distributed close to the “center-region” of the internucleoside linkages, e.g., the 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 centermost linkages. For example, a 16, 17, 18, 19, 20, 21, 22, 23, or 24-mer oligomer may have at least 50%, 60%, 70%, or 80% of the total cationic linkages localized to the 8, 9, 10, 11, or 12 centermost linkages. 
     B. Chemistry Features 
     The modified antisense oligomers may contain a variety of nucleotide analog subunits. Further examples include: 
     phosphoramidate containing oligomers, 
     phosphorodiamidate containing oligomers, 
     phosphorotriamidate containing oligomers, 
     phosphorothioate containing oligomers, 
     morpholino containing oligomers optionally substituted with a phosphoramidate internucleoside linkage or a phosphorodiamidate internucleoside linkage, 
     2′O-methyl containing oligomers optionally substituted with a phosphorothioate internucleoside linkage, 
     locked nucleic acid (LNA) containing oligomers optionally substituted with a phosphorothioate internucleoside linkage, 
     2′ O-methoxyethyl (MOE) containing oligomers optionally substituted with a phosphorothioate internucleoside linkage, 
     2′-fluoro-containing oligomers optionally substituted with a phosphorothioate internucleoside linkage, 
     2′O,4′C-ethylene-bridged nucleic acids (ENAs) containing oligomers optionally substituted with a phosphorothioate internucleoside linkage, 
     tricyclo-DNA (tc-DNA) containing oligomers optionally substituted with a phosphorothioate internucleoside linkage, 
     2′-O-[2-(N-methylcarbamoyl)ethyl]containing oligomers optionally substituted with a phosphorothioate internucleoside linkage, 
     morpholino containing oligomers further comprising a phosphorodiamidate internucleoside linkage wherein the phosphorous atom of the phosphorodiamidate is covalently bonded to the nitrogen atom of a morpholino ring, and is covalently bonded to a (1,4-piperazin)-1-yl moiety or to a substituted (1,4-piperazin)-1-yl (PMOplus) moiety, 
     morpholino containing oligomers further comprising a phosphorodiamidate internucleoside linkage wherein the phosphorus atom of the phosphorodiamidate is covalently bonded to the nitrogen atom of a morpholino ring and is covalently bonded to a 4-aminopiperdin-1-yl moiety (i.e., APN) or a substituted 4-aminopiperdin-1-yl (PMO-X) moiety, 
     a morpholino subunit further comprising a phosphorodiamidate internucleoside linkage where a phosphorus atom of the phosphorodiamidate is covalently bonded to the nitrogen atom of the morpholino ring, and is covalently bonded to a dimethylamino moiety, 
     ribose sugar containing oligomers further comprising a phosphorothioate internucleoside linkage or a phosphoramidate internucleoside linkage, 
     deoxyribose sugar containing oligomers further comprising a phosphorothioate internucleoside linkage oligomer or a phosphoramidate internucleoside linkage, 
     peptide-conjugated phosphorodiamidate morpholino containing oligomers (PPMO) which are further optionally substituted, 
     peptide nucleic acid (PNA) oligomers which are further optionally substituted including further substitutions, 
     and combinations of any of the foregoing. 
     In certain embodiments, the phosphorous atom of a phosphorodiamidate linkage is further substituted with a (1,4-piperazin)-1-yl moiety, a substituted (1,4-piperazin)-1-yl moiety, a 4-aminopiperidin-1-yl moiety, or a substituted 4-aminopiperidin-1-yl moiety. 
     In general, PNA and LNA chemistries can utilize shorter targeting sequences because of their relatively high target binding strength relative to PMO and 2′O-Me oligomers. Phosphorothioate and 2′O-Me chemistries can be combined to generate a 2′O-Me-phosphorothioate analog. See, e.g., PCT Publication Nos. WO/2013/112053 and WO/2009/008725, which are hereby incorporated by reference in their entireties. 
     In some instances, modified antisense oligomers, such as phosphorodiamidate morpholino oligomers (PMO), can be conjugated to cell penetrating peptides (CPPs) to facilitate intracellular delivery. Peptide-conjugated PMOs are called PPMOs and certain embodiments include those described in PCT Publication No. WO/2012/150960, which is hereby incorporated by reference in its entirety. In some embodiments, an arginine-rich peptide sequence conjugated or linked to, for example, the 3′ terminal end of a modified antisense oligomer as described herein may be used. 
     1. Peptide Nucleic Acids (PNAs) 
     Peptide nucleic acids (PNAs) are analogs of DNA in which the backbone is structurally homomorphous with a deoxyribose backbone, consisting of N-(2-aminoethyl) glycine units to which pyrimidine or purine bases are attached. PNAs containing natural pyrimidine and purine bases hybridize to complementary oligomers obeying Watson-Crick base-pairing rules, and mimic DNA in terms of base pair recognition (Egholm, Buchardt et al. 1993). The internucleoside linkages of PNAs are formed by peptide bonds rather than phosphodiester bonds, making them well-suited for antisense applications (see structure below). The backbone is uncharged, resulting in PNA/DNA or PNA/RNA duplexes that exhibit greater than normal thermal stability. PNAs are not recognized by nucleases or proteases. A non-limiting example of a PNA oligomer comprising PNA subunits is depicted below: 
     
       
         
         
             
             
         
       
     
     Despite a radical structural change to the natural structure, PNAs are capable of sequence-specific binding in a helix form to DNA or RNA. Characteristics of PNAs include a high binding affinity to complementary DNA or RNA, a destabilizing effect caused by single-base mismatch, resistance to nucleases and proteases, hybridization with DNA or RNA independent of salt concentration and triplex formation with homopurine DNA. PANAGENE (Daejeon, Korea) has developed Bts PNA monomers (Bts; benzothiazole-2-sulfonyl group) and oligomerization process. The PNA oligomerization using Bts PNA monomers is composed of repetitive cycles of deprotection, coupling and capping. PNAs can be produced synthetically using any technique known in the art. See, e.g., U.S. Pat. Nos. 6,969,766, 7,211,668, 7,022,851, 7,125,994, 7,145,006 and 7,179,896. See also U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262 for the preparation of PNAs. Further teaching of PNA compounds can be found in Nielsen et al., Science, 254:1497-1500, 1991. Each of the foregoing is hereby incorporated by reference in its entirety. 
     2. Locked Nucleic Acids (LNAs) 
     Modified antisense oligomer compounds may also contain “locked nucleic acid” subunits (LNAs). “LNAs” are a member of a class of modifications called bridged nucleic acid (BNA). BNA is characterized by a covalent linkage that locks the conformation of the ribose ring in a C30-endo (northern) sugar pucker. For LNA, the bridge is composed of a methylene between the 2′-O and the 4′-C positions. LNA enhances backbone preorganization and base stacking to increase hybridization and thermal stability. 
     The structures of LNAs can be found, for example, in Wengel, et al., Chemical Communications (1998) 455; Tetrahedron (1998) 54:3607, and Accounts of Chem. Research (1999) 32:301); Obika, et al., Tetrahedron Letters (1997) 38:8735; (1998) 39:5401, and Bioorganic Medicinal Chemistry (2008) 16:9230, which are hereby incorporated by reference in their entirety. A non-limiting example of an LNA oligomer comprising LNA subunits and phosphodiester internucleoside linkages is depicted below: 
     
       
         
         
             
             
         
       
     
     Compounds of the disclosure may incorporate one or more LNAs; in some cases, the compounds may be entirely composed of LNAs. Methods for the synthesis of individual LNA nucleoside subunits and their incorporation into oligomers are described, for example, in U.S. Pat. Nos. 7,572,582, 7,569,575, 7,084,125, 7,060,809, 7,053,207, 7,034,133, 6,794,499, and 6,670,461, which are hereby incorporated by reference in their entirety. Typical internucleoside linkers include phosphodiester and phosphorothioate moieties; alternatively, non-phosphorous containing linkers may be employed. Further embodiments include an LNA containing compound where each LNA subunit is separated by a DNA subunit. Certain compounds are composed of alternating LNA and DNA subunits where the internucleoside linker is phosphorothioate. 
     2′O,4′C-ethylene-bridged nucleic acids (ENAs) are another member of the class of BNAs. A non-limiting example of an ENA subunit and phosphodiester internucleoside linkage is depicted below: 
     
       
         
         
             
             
         
       
     
     ENA oligomers and their preparation are described in Obika et al., Tetrahedron Ltt 38(50): 8735, which is hereby incorporated by reference in its entirety. Compounds of the disclosure may incorporate one or more ENA subunits. 
     3. Phosphorothioates 
     “Phosphorothioates” (or S-oligos) are a variant of native DNA or RNA in which one of the nonbridging oxygens of the phosphodiester internucleoside linkages is replaced by sulfur. A non-limiting example of a phosphorothioate DNA (left), comprising deoxyribose subunits and phosphorothioate internucleoside linkages, and phosphorothioate RNA (right), comprising ribose subunits and phosophorothioate internucleoside linkages, are depicted below: 
     
       
         
         
             
             
         
       
     
     The sulfurization of the internucleoside bond reduces the action of endo- and exonucleases including 5′ to 3′ and 3′ to 5′ DNA POL 1 exonuclease, nucleases S1 and P1, RNases, serum nucleases and snake venom phosphodiesterase. Phosphorothioates may be made by two principal routes: by the action of a solution of elemental sulfur in carbon disulfide on a hydrogen phosphonate, or by the method of sulfurizing phosphite triesters with either tetraethylthiuram disulfide (TETD) or 3H-1, 2-bensodithiol-3-one 1, 1-dioxide (BDTD) (see, e.g., Iyer et al., J. Org. Chem. 55, 4693-4699, 1990, which are hereby incorporated by reference in their entirety). The latter methods avoid the problem of elemental sulfur&#39;s insolubility in most organic solvents and the toxicity of carbon disulfide. The TETD and BDTD methods also yield higher purity phosphorothioates. 
     4. Tricyclo-DNAs and Tricyclo-Phosphorothioate Nucleotides 
     Tricyclo-DNAs (tc-DNA) are a class of constrained DNA analogs in which each nucleotide is modified by the introduction of a cyclopropane ring to restrict conformational flexibility of the backbone and to optimize the backbone geometry of the torsion angle γ. Homobasic adenine- and thymine-containing tc-DNAs form extraordinarily stable A-T base pairs with complementary RNAs. Tricyclo-DNAs and their synthesis are described in PCT Publication No. WO 2010/115993, which is hereby incorporated by reference in its entirety. Compounds of the disclosure may incorporate one or more tricyclo-DNA subunits; in some cases, the compounds may be entirely composed of tricyclo-DNA subunits. 
     Tricyclo-phosphorothioate nucleotides are tricyclo-DNA subunits with phosphorothioate internucleoside linkages. Tricyclo-phosphorothioate nucleotides and their synthesis are described in PCT Publication No. WO 2013/053928, which is hereby incorporated by reference in its entirety. Compounds of the disclosure may incorporate one or more tricyclo-DNA subunits; in some cases, the compounds may be entirely composed of tricyclo-DNA nucleotides. A non-limiting example of a tricyclo-DNA/tricycle subunit and phosphodiester internucleoside linkage is depicted below: 
     
       
         
         
             
             
         
       
     
     5. 2′ O-Methyl, 2′ O-MOE, and 2′-F Oligomers 
     “2′O-Me oligomer” molecules comprise subunits that carry a methyl group at the 2′-OH residue of the ribose molecule. 2′-O-Me-RNAs show the same (or similar) behavior as DNA, but are protected against nuclease degradation. 2′-O-Me-RNAs can also be combined with phosphorothioate oligomers (PTOs) for further stabilization. 2′O-Me oligomers (wherein the 2′-OMe subunits are connected by phosphodiester or phosphorothioate internucleoside linkages) can be synthesized according to routine techniques in the art (see, e.g., Yoo et al., Nucleic Acids Res. 32:2008-16, 2004, which is hereby incorporated by reference in its entirety). A non-limiting example of a 2′ O-Me oligomer comprising 2′-OMe subunits and phosphodiester intersubunit linkages is depicted below: 
     
       
         
         
             
             
         
       
     
     2′ O-Me oligomers may also comprise a phosphorothioate linkage (2′ O-Me phosphorothioate oligomers). 2′ O-Methoxyethyl Oligomers (2′-O MOE), like 2′ O-Me oligomers, comprise subunits that carry a methoxyethyl group at the 2′-OH residue of the ribose molecule and are discussed in Martin et al., Helv. Chim. Acta, 78, 486-504, 1995, which is hereby incorporated by reference in its entirety. A non-limiting example of a 2′ O-MOE subunit is depicted below: 
     
       
         
         
             
             
         
       
     
     In contrast to the preceding alkylated 2′OH ribose derivatives, 2′-fluoro oligomers comprise subunits that have a fluoro radical in at the 2′ position in place of the 2′OH. A non-limiting example of a 2′-F oligomer comprising 2′-F subunits and phosphodiester internucleoside linkages is depicted below: 
     
       
         
         
             
             
         
       
     
     2′-fluoro oligomers are further described in WO 2004/043977, which is hereby incorporated by reference in its entirety. Compounds of the disclosure may incorporate one or more 2′O-Methyl, 2′ O-MOE, and 2′ F subunits and may utilize any of the internucleoside linkages described here. In some instances, a compound of the disclosure could be composed of entirely 2′O-Methyl, 2′ O-MOE, or 2′ F subunits. One embodiment of a compound of the disclosure is composed entirely of 2′O-methyl subunits. 
     6. 2′-O-[2-(N-methylcarbamoyl)ethyl] Oligomers (MCEs) 
     MCEs are another example of 2′O modified ribonucleotides useful in the compounds of the disclosure. Here, the 2′OH is derivatized to a 2-(N-methylcarbamoyl)ethyl moiety to increase nuclease resistance. A non-limiting example of an MCE oligomer comprising MCE subunits and phosphodiester internucleoside linkages is depicted below: 
     
       
         
         
             
             
         
       
     
     MCEs and their synthesis are described in Yamada et al., J. Org. Chem., 76(9):3042-53, which is hereby incorporated by reference in its entirety. Compounds of the disclosure may incorporate one or more MCE subunits. 
     7. Morpholino-Based Oligomers 
     Morpholino-based oligomers refer to an oligomer comprising morpholino subunits supporting a nucleobase and, instead of a ribose, contains a morpholinyl ring. Exemplary internucleoside linkages include, for example, phosphoramidate or phosphorodiamidate internucleoside linkages joining the morpholinyl ring nitrogen of one morpholino subunit to the 4′ exocyclic carbon of an adjacent morpholino subunit. Each morpholino subunit comprises a purine or pyrimidine nucleobase effective to bind, by base-specific hydrogen bonding, to a base in an oligonucleotide. 
     Morpholino-based oligomers (including modified antisense oligomers) are detailed, for example, in U.S. Pat. Nos. 5,698,685; 5,217,866; 5,142,047; 5,034,506; 5,166,315; 5,185,444; 5,521,063; 5,506,337 and pending U.S. patent application Ser. Nos. 12/271,036; 12/271,040; and PCT Publication No. WO/2009/064471 and WO/2012/043730 and Summerton et al. 1997, Antisense and Nucleic Acid Drug Development, 7, 187-195, which are hereby incorporated by reference in their entirety. The term “morpholino subunit,” is used herein as described in Summerton et al. 
     Within the oligomer structure, the phosphate groups are commonly referred to as forming the “internucleoside linkages” of the oligomer. The naturally occurring intemucleoside linkage of RNA and DNA is a 3′ to 5′ phosphodiester linkage. A “phosphoramidate” group comprises phosphorus having three attached oxygen atoms and one attached nitrogen atom, while a “phosphorodiamidate” group comprises phosphorus having two attached oxygen atoms and two attached nitrogen atoms. A “phosphorotriamidate” group (or a phosphoric acid triamide group) comprises phosphorus having one attached oxygen atom and three attached nitrogen atoms. In the uncharged or the cationic intemucleoside linkages of the morpholino-based oligomers described herein, one nitrogen is always pendant to the linkage chain. The second nitrogen, in a phosphorodiamidate linkage, is typically the ring nitrogen in a morpholino ring structure. 
     “PMO” refers to phosphorodiamidate morpholino-based oligomers having a phosphorus atom with (i) a covalent bond to the nitrogen atom of a morpholino ring and (ii) a second covalent bond to the nitrogen of a dimethylamino. “PMO-X” refers to phosphorodiamidate morpholino-based oligomers having a phosphorus atom with (i) a covalent bond to the nitrogen atom of a morpholino ring and (ii) a second covalent bond to the ring nitrogen of, for example, a 4-aminopiperdin-1-yl (i.e., APN) or a derivative of 4-aminopiperdin-1-yl. Exemplary PMO-X oligomers are disclosed in PCT Application No. PCT/US2011/38459 and PCT Publication No. WO 2013/074834, which are hereby incorporated by reference in their entirety. PMO-X includes “PMO-apn,” “PMO-APN” or “APN,” which refers to a PMO-X oligomer which comprises at least one internucleoside linkage where a phosphorus atom is linked to a morpholino group and to the ring nitrogen of a 4-aminopiperdin-1-yl (i.e., APN). In specific embodiments, a modified antisense oligomer comprising a targeting sequence as set forth in Tables 3 and 4 comprises at least one APN-containing linkage or APN derivative-containing linkage. Various embodiments include morpholino-based oligomers that have about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% APN/APN derivative-containing linkages, where the remaining linkages (if less than 100%) are uncharged linkages, e.g., about or at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 of the total internucleoside linkages are APN/APN derivative-containing linkages.
         In various embodiments, the modified antisense oligomer is a compound of formula (I):       

     
       
         
         
             
             
         
       
         
         
           
             or a pharmaceutically acceptable salt thereof, wherein: 
             each Nu is a nucleobase which taken together forms a targeting sequence; 
             Z is an integer from 8 to 48; 
             each Y is independently selected from 0 and —NR 4 , wherein each R 4  is independently selected from H, C 1 -C 6  alkyl, aralkyl, —C(═NH)NH 2 , —C(O)(CH 2 ) n NR 5 C(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 5 C(═NH)NH 2 , and G, wherein R 5  is selected from H and C 1 -C 6  alkyl and n is an integer from 1 to 5; 
             T is selected from OH and a moiety of the formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein:
           A is selected from —OH, —N(R 7 ) 2 R 8 , wherein:   each R 7  is independently selected from H and C 1 -C 6  alkyl, and   R 8  is selected from an electron pair and H, and   R 6  is selected from OH, —N(R 9 )CH 2 C(O)NH 2 , and a moiety of the formula:   
         
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein:
           R 9  is selected from H and C 1 -C 6  alkyl; and   R 10  is selected from G, —C(O)—R 11 OH, acyl, trityl, 4-methoxytrityl, —C(═NH)NH 2 , —C(O)(CH 2 ) m NR 12 C(═NH)NH 2 , and —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 12 C(═NH)NH 2 , wherein:   m is an integer from 1 to 5,   R 11  is of the formula —(O-alkyl) y - wherein y is an integer from 3 to 10 and each of they alkyl groups is independently selected from C 2 -C 6  alkyl; and   R 12  is selected from H and C 1 -C 6  alkyl;   each instance of R 1  is independently selected from:   —N(R 13 ) 2 R 14  wherein each R 13  is independently selected from H and C 1 -C 6  alkyl, and R 14  is selected from an electron pair and H;   
         
             a moiety of formula (II): 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein:
           R 15  is selected from H, G, C 1 -C 6  alkyl, —C(═NH)NH 2 , —C(O)(CH 2 ) q NR 18 C(═NH)NH 2 , and —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 18 C(═NH)NH 2 , wherein:   R 18  is selected from H and C 1 -C 6  alkyl; and   q is an integer from 1 to 5,   
         
             R 16  is selected from an electron pair and H; and 
             each R 17  is independently selected from H and methyl; and 
             a moiety of formula (III): 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein:
           R 19  is selected from H, C 1 -C 6  alkyl, —C(═NH)NH 2 , —C(O)(CH 2 ) r NR 22 C(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 22 C(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 ) 4 NH 2 , and G   
         
             wherein:
           R 22  is selected from H and C 1 -C 6  alkyl; and   r is an integer from 1 to 5,   
         
             R 20  is selected from H and C 1 -C 6  alkyl; and 
             R 21  is selected from an electron pair and H; and 
             R 2  is selected from H, G, acyl, trityl, 4-methoxytrityl, C 1 -C 6  alkyl, —C(═NH)NH 2 , —C(O)—R 23 , —C(O)(CH 2 ) s NR 24 C(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 24 C(═NH)NH 2 , —C(O)CH(NH 2 )(CH 2 ) 3 NHC(═NH)N 
             H 2 , and a moiety of the formula: 
           
         
       
    
     
       
         
         
             
             
         
       
     
     wherein,
         R 23  is of the formula —(O-alkyl) v -OH, wherein v is an integer from 3 to 10 and each of the v alkyl groups is independently selected from C 2 -C 6  alkyl; and   R 24  is selected from H and C 1 -C 6  alkyl;   s is an integer from 1 to 5;   L is selected from —C(O)(CH 2 ) 6 C(O)— and —C(O)(CH 2 ) 2 S 2 (CH 2 ) 2 C(O)—; and   each R 25  is of the formula —(CH 2 ) 2 OC(O)N(R 26 ) 2  wherein each R 26  is of the formula —(CH 2 ) 6 NHC(═NH)NH 2 , and       

     R 3  is selected from an electron pair, H, and C 1 -C 6  alkyl,
         wherein G is a cell penetrating peptide (“CPP”) and linker moiety selected from —C(O)(CH 2 ) 5 NH—CPP, —C(O)(CH 2 ) 2 NH—CPP, —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NH—CPP,   and —C(O)CH 2 NH—CPP, or G is of the formula:       

     
       
         
         
             
             
         
       
         
         
           
             wherein the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus, with the proviso that up to one instance of G is present. 
           
         
       
    
     In various embodiments, the targeting sequence is complementary to a target region within myostatin pre-mRNA. In some embodiments, the targeting sequence is complementary to 12 or more contiguous nucleotides in a target region entirely within exon 2 where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 2 to 3) of myostatin pre-mRNA. 
     In various embodiments, the targeting sequence is complementary to a target region within dystrophin pre-mRNA. In some embodiments, the targeting sequence is complementary to 10 or more contiguous nucleotides in a target region within an exon of dystrophin pre-mRNA selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. In embodiments, the target region is entirely within an exon of dystrophin pre-mRNA where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction of dystrophin pre-mRNA. 
     In various embodiments, the myostatin targeting sequence comprises one of SEQ ID NOS: 16 to 75, is selected from one of SEQ ID NOS: 16 to 75, is a fragment of at least 12 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 16 to 75, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 16 to 75, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 16 to 75 is thymine (T), and each Y of SEQ ID NOS: 16 to 75 is cytosine (C). 
     In some embodiments, the myostatin targeting sequence of formula (I) is selected from: 
     
       
         
           
               
               
            
               
                   
                 a) 
               
            
           
           
               
            
               
                 SEQ ID NO: 71 
               
            
           
           
               
               
            
               
                   
                 (YYAGYYYAXYXXYXYYXGGXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 b) 
               
            
           
           
               
            
               
                 SEQ ID NO: 72 
               
            
           
           
               
               
            
               
                   
                 (YAYXXAYYAGYYYAXYXXYXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 c) 
               
            
           
           
               
            
               
                 SEQ ID NO: 73 
               
            
           
           
               
               
            
               
                   
                 (YYAYXXGYAXXAGAAAAXYAGY) wherein Z is 22; 
               
               
                   
                   
               
               
                   
                 d) 
               
            
           
           
               
            
               
                 SEQ ID NO: 74 
               
            
           
           
               
               
            
               
                   
                 (GYATTAGAAAATYAGYTATAAATG) wherein Z is 24; 
               
               
                   
                 and 
               
               
                   
                   
               
               
                   
                 e) 
               
            
           
           
               
            
               
                 SEQ ID NO: 75 
               
            
           
           
               
               
            
               
                   
                 (YYATYYGYTTGYATTAGAAAGTYAGY) wherein Z is 26; 
               
            
           
         
       
         
         
           
             wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 71 to 75 is thymine (T), and each Y of SEQ ID NOS: 71 to 75 is cytosine (C). 
           
         
       
    
     In various embodiments, the dystrophin targeting sequence comprises one of SEQ ID NOS: 76 to 3485, is selected from one of SEQ ID NOS: 76 to 3485, is a fragment of at least 10 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 76 to 3485, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 76 to 3485, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 76 to 3485 is thymine (T), and each Y of SEQ ID NOS: 76 to 3485 is cytosine (C). In some embodiments, a targeting sequence may comprise SEQ ID NO: 76. 
     In various embodiments, at least one X of the targeting sequence is T. In various embodiments, each X of the targeting sequence is T. 
     In various embodiments, at least one X of the targeting sequence is U. In various embodiments, each X of the targeting sequence is U. 
     In various embodiments, at least one Y of the targeting sequence is 5 mC. In various embodiments, each Y of the targeting sequence is 5 mC. 
     In various embodiments, at least one Y of the targeting sequence is C. In various embodiments, each Y of the targeting sequence is C. 
     In various embodiments, at least one X of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is T. In various embodiments, each X of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is T. 
     In various embodiments, at least one X of the targeting sequence is U. In various embodiments, each X of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is U. 
     In various embodiments, at least one Y of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is 5 mC. In various embodiments, each Y of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is 5 mC. 
     In various embodiments, at least one Y of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is C. In various embodiments, each Y of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is C. 
     In some embodiments, R 3  is a moiety of the formula: 
     
       
         
         
             
             
         
       
         
         
           
             where L is selected from —C(O)(CH 2 ) 6 C(O)— or —C(O)(CH 2 ) 2 S 2 (CH 2 ) 2 C(O)—, and each R 25  is of the formula —(CH 2 ) 2 OC(O)N(R 26 ) 2  wherein each R 26  is of the formula —(CH 2 ) 6 NHC(═NH)NH 2 . Such moieties are further described in U.S. Pat. No. 7,935,816, which is hereby incorporated by reference in its entirety. 
           
         
       
    
     In certain embodiments, R 3  may comprise either moiety depicted below: 
     
       
         
         
             
             
         
       
     
     In various embodiments, each Y is O, R 2  is selected from H or G, R 3  is selected from an electron pair or H. In some embodiments, R 2  is G wherein the CPP is of a sequence selected from SEQ ID NOS: 3486 to 3501. In certain embodiments, R 2  is H. 
     In certain embodiments, each R 1  is —N(CH 3 ) 2 . In some embodiments, about 50-90% of the R 1  groups are dimethylamino (i.e. —N(CH 3 ) 2 ). In certain embodiments, about 70% to about 80% of the R 1  groups are dimethylamino. In certain embodiments about 75% of the R 1  groups are dimethylamino. In certain embodiments, about 66% of the R 1  groups are dimethylamino. 
     In some embodiments of the disclosure, R 1  may be selected from: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, at least one R 1  is: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, T is of the formula: 
     
       
         
         
             
             
         
       
     
     wherein A is —N(CH 3 ) 2 , and R 6  is of the formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R 10  is —C(O)R 11 OH. 
           
         
       
    
     In some embodiments, each Y is O, and T is selected from: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, T is of the formula: 
     
       
         
         
             
             
         
       
     
     In various embodiments, each Y is O, and R 2  is selected from H or G, R 3  is selected from an electron pair or H. In some embodiments, R 2  is G, wherein the CPP is of a sequence selected from SEQ ID NOS: 3486 to 3501 described below.
         In other embodiments, the modified antisense oligomer is a compound of formula (IV):       

     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, where:
         each Nu is a nucleobase which taken together forms a targeting sequence;   Z is an integer from 8 to 48;   each Y is independently selected from O and —NR 4 , wherein each R 4  is independently selected from H, C 1 -C 6  alkyl,
 
aralkyl, —C(═NH)NH 2 , —C(O)(CH 2 ) n NR 5 C(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 5 C(═NH)NH 2 , and G, wherein R 5  is selected from H and C 1 -C 6  alkyl and n is an integer from 1 to 5;
       

     T is selected from OH and a moiety of the formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein: 
             A is selected from —OH and —N(R 7 ) 2 R 8 , wherein:
           each R 7  is independently selected from H and C 1 -C 6  alkyl, and   R 8  is selected from an electron pair and H, and   
         
             R 6  is selected from OH, —N(R 9 )CH 2 C(O)NH 2 , and a moiety of the formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein:
           R 9  is selected from H and C 1 -C 6  alkyl; and   R 10  is selected from G, —C(O)—R 11 OH, acyl, trityl, 4-methoxytrityl, —C(═NH)NH 2 , —C(O)(CH 2 ) m NR 12 C(═NH)NH 2 , and —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 12 C(═NH)NH 2 , wherein:
               m is an integer from 1 to 5,   R 11  is of the formula —(O-alkyl) y - wherein y is an integer from 3 to 10 and
                   each of the y alkyl groups is independently selected from C 2 -C 6  alkyl; and   
                   
               
         
           
         
       
    
     R 12  is selected from H and C 1 -C 6  alkyl; 
     R 2  is selected from H, G, acyl, trityl, 4-methoxytrityl, C 1 -C 6  alkyl, —C(═NH)NH 2 , and —C(O)—R 23 ; and 
     R 3  is selected from an electron pair, H, and C 1 -C 6  alkyl. 
     In various embodiments, the targeting sequence is complementary to a target region within myostatin pre-mRNA. In some embodiments, the targeting sequence is complementary to 12 or more contiguous nucleotides in a target region entirely within exon 2 where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 1 to 3) of myostatin pre-mRNA. 
     In various embodiments, the targeting sequence is complementary to a target region within dystrophin pre-mRNA. In some embodiments, the targeting sequence is complementary to 10 or more contiguous nucleotides in a target region within an exon of dystrophin pre-mRNA selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. In embodiments, the target region is entirely within an exon of dystrophin pre-mRNA where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 76 to 3485) of dystrophin pre-mRNA. 
     In various embodiments, the myostatin targeting sequence comprises one of SEQ ID NOS: 4 to 15, is selected from one of SEQ ID NOS: 4 to 15, is a fragment of at least 12 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 4 to 15, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 4 to 15, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 4 to 15 is thymine (T), and each Y of SEQ ID NOS: 4 to 15 is cytosine (C).
         In some embodiments, the myostaton targeting sequence of formula (IV) is selected from:       

     
       
         
           
               
               
            
               
                   
                 a) 
               
            
           
           
               
            
               
                 SEQ ID NO: 71 
               
            
           
           
               
               
            
               
                   
                 (YYAGYYYAXYXXYXYYXGGXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 b) 
               
            
           
           
               
            
               
                 SEQ ID NO: 72 
               
            
           
           
               
               
            
               
                   
                 (YAYXXAYYAGYYYAXYXXYXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 c) 
               
            
           
           
               
            
               
                 SEQ ID NO: 73 
               
            
           
           
               
               
            
               
                   
                 (YYAYXXGYAXXAGAAAAXYAGY) wherein Z is 22; 
               
               
                   
                   
               
               
                   
                 d) 
               
            
           
           
               
            
               
                 SEQ ID NO: 74 
               
            
           
           
               
               
            
               
                   
                 (GYATTAGAAAATYAGYTATAAATG) wherein Z is 24; 
               
               
                   
                 and 
               
               
                   
                   
               
               
                   
                 e) 
               
            
           
           
               
            
               
                 SEQ ID NO: 75 
               
            
           
           
               
               
            
               
                   
                 (YYATYYGYTTGYATTAGAAAGTYAGY) wherein Z is 26; 
               
            
           
         
       
         
         
           
             wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 71 to 75 is thymine (T), and each Y of SEQ ID NOS: 71 to 75 is cytosine (C). 
           
         
       
    
     In various embodiments, the dystrophin targeting sequence comprises one of SEQ ID NOS: 76 to 3485, is selected from one of SEQ ID NOS: 76 to 3485, is a fragment of at least 10 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 76 to 3485, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 76 to 3485, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 76 to 3485 is thymine (T), and each Y of SEQ ID NOS: 76 to 3485 is cytosine (C). In some embodiments, a targeting sequence may comprise SEQ ID NO: 76. 
     In various embodiments, Y is O, R 2  is selected from H or G, R 3  is selected from an electron pair or H. In some embodiments, R 2  is G, wherein the CPP is of a sequence selected from SEQ ID NOS: 9-24. In certain embodiments, R 2  is H. 
     In some embodiments, Y is O, and T is selected from: 
     
       
         
         
             
             
         
       
     
     In some embodiments, T is of the formula: 
     
       
         
         
             
             
         
       
     
     R 2  is hydrogen; and R 3  is an electron pair.
         In other embodiments, the modified antisense oligomer is a compound of formula (V):       

     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
         each Nu is a nucleobase which taken together forms a targeting sequence;   Z is an integer from 8 to 48;   each Y is independently selected from 0 and —NR 4 , wherein each R 4  is independently selected from H, C 1 -C 6  alkyl, aralkyl, —C(═NH)NH 2 , —C(O)(CH 2 ) n NR 5 C(═NH)NH 2 , —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 5 C(═NH)NH 2 , and G, wherein R 5  is selected from H and C 1 -C 6  alkyl and n is an integer from 1 to 5;   T is selected from OH and a moiety of the formula:       

     
       
         
         
             
             
         
       
     
     wherein:
         A is selected from —OH, —N(R 7 ) 2 R 8 , wherein:   each R 7  is independently selected from H and C 1 -C 6  alkyl, and   R 8  is selected from an electron pair and H, and   R 6  is selected from OH, —N(R 9 )CH 2 C(O)NH 2 , and a moiety of the formula:       

     
       
         
         
             
             
         
       
     
     wherein:
         R 9  is selected from H and C 1 -C 6  alkyl; and   R 10  is selected from G, —C(O)—R 11 OH, acyl, trityl, 4-methoxytrityl, —C(═NH)NH 2 , —C(O)(CH 2 ) m NR 12 C(═NH)NH 2 , and —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NR 12 C(═NH)NH 2 , wherein:   m is an integer from 1 to 5,   R 11  is of the formula —(O-alkyl) y - wherein y is an integer from 3 to 10 and each of they alkyl groups is independently selected from C 2 -C 6  alkyl; and   R 12  is selected from H and C 1 -C 6  alkyl;   wherein G is a cell penetrating peptide (“CPP”) and linker moiety selected from —C(O)(CH 2 ) 5 NH—CPP, —C(O)(CH 2 ) 2 NH—CPP, —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NH—CPP,       

     and —C(O)CH 2 NH—CPP, or G is of the formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus, with the proviso that up to one instance of G is present. 
           
         
       
    
     In various embodiments, the targeting sequence is complementary to a target region within myostatin pre-mRNA. In some embodiments, the targeting sequence is complementary to 12 or more contiguous nucleotides in a target region entirely within exon 2 where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 1 to 3) of myostatin pre-mRNA. 
     In various embodiments, the targeting sequence is complementary to a target region within dystrophin pre-mRNA. In some embodiments, the targeting sequence is complementary to 10 or more contiguous nucleotides in a target region within an exon of dystrophin pre-mRNA selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. In embodiments, the target region is entirely within an exon of dystrophin pre-mRNA where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 4 to 15) of dystrophin pre-mRNA. 
     In various embodiments, the myostatin targeting sequence comprises one of SEQ ID NOS: 16 to 75, is selected from one of SEQ ID NOS: 16 to 75, is a fragment of at least 12 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 16 to 75, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 16 to 75, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 16 to 75 is thymine (T), and each Y of SEQ ID NOS: 16 to 75 is cytosine (C).
         In some embodiments, the myostatin targeting sequence of formula (V) is selected from:       

     
       
         
           
               
               
            
               
                   
                 a) 
               
            
           
           
               
            
               
                 SEQ ID NO: 71 
               
            
           
           
               
               
            
               
                   
                 (YYAGYYYAXYXXYXYYXGGXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 b) 
               
            
           
           
               
            
               
                 SEQ ID NO: 72 
               
            
           
           
               
               
            
               
                   
                 (YAYXXAYYAGYYYAXYXXYXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 c) 
               
            
           
           
               
            
               
                 SEQ ID NO: 73 
               
            
           
           
               
               
            
               
                   
                 (YYAYXXGYAXXAGAAAAXYAGY) wherein Z is 22; 
               
               
                   
                   
               
               
                   
                 d) 
               
            
           
           
               
            
               
                 SEQ ID NO: 74 
               
            
           
           
               
               
            
               
                   
                 (GYATTAGAAAATYAGYTATAAATG) wherein Z is 24; 
               
               
                   
                 and 
               
               
                   
                   
               
               
                   
                 e) 
               
            
           
           
               
            
               
                 SEQ ID NO: 75 
               
            
           
           
               
               
            
               
                   
                 (YYATYYGYTTGYATTAGAAAGTYAGY) wherein Z is 26; 
               
            
           
         
       
         
         
           
             wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 71 to 75 is thymine (T), and each Y of SEQ ID NOS: 71 to 75 is cytosine (C). 
           
         
       
    
     In various embodiments, the dystrophin targeting sequence comprises one of SEQ ID NOS: 76 to 3485, is selected from one of SEQ ID NOS: 76 to 3485, is a fragment of at least 10 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 76 to 3485, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 76 to 3485, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 76 to 3485 is thymine (T), and each Y of SEQ ID NOS: 76 to 3485 is cytosine (C). In some embodiments, a targeting sequence may comprise SEQ ID NO: 76. 
     In various embodiments, each Y is O, and T is selected from: 
     
       
         
         
             
             
         
       
     
     In some embodiments, T is of the formula: 
     
       
         
         
             
             
         
       
     
     In certain embodiments, the antisense oligomer of the disclosure is a compound of formula (VI): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, where:
         each Nu is a nucleobase which taken together form a targeting sequence;   Z is an integer from 15 to 25;   each Y is O;   each R 1  is independently selected from:       

     
       
         
         
             
             
         
       
     
     In various embodiments, at least one R 1  is —N(CH 3 ) 2 . In some embodiments, each R 1  is —N(CH 3 ) 2 . 
     In various embodiments, the targeting sequence is complementary to a target region within myostatin pre-mRNA. In some embodiments, the targeting sequence is complementary to 12 or more contiguous nucleotides in a target region entirely within exon 2 where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 1 to 3) of myostatin pre-mRNA. 
     In various embodiments, the targeting sequence is complementary to a target region within dystrophin pre-mRNA. In some embodiments, the targeting sequence is complementary to 10 or more contiguous nucleotides in a target region within an exon of dystrophin pre-mRNA selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. In embodiments, the target region is entirely within an exon of dystrophin pre-mRNA where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 4 to 15) of dystrophin pre-mRNA. 
     In various embodiments, the myostatin targeting sequence comprises one of SEQ ID NOS: 16 to 75, is selected from one of SEQ ID NOS: 16 to 75, is a fragment of at least 12 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 16 to 75, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 16 to 75, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 16 to 75 is thymine (T), and each Y of SEQ ID NOS: 16 to 75 is cytosine (C).
         In some embodiments, the myostatin targeting sequence of formula (VI) is selected from:       

     
       
         
           
               
               
            
               
                   
                 a) 
               
            
           
           
               
            
               
                 SEQ ID NO: 71 
               
            
           
           
               
               
            
               
                   
                 (YYAGYYYAXYXXYXYYXGGXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 b) 
               
            
           
           
               
            
               
                 SEQ ID NO: 72 
               
            
           
           
               
               
            
               
                   
                 (YAYXXAYYAGYYYAXYXXYXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 c) 
               
            
           
           
               
            
               
                 SEQ ID NO: 73 
               
            
           
           
               
               
            
               
                   
                 (YYAYXXGYAXXAGAAAAXYAGY) wherein Z is 22; 
               
               
                   
                   
               
               
                   
                 d) 
               
            
           
           
               
            
               
                 SEQ ID NO: 74 
               
            
           
           
               
               
            
               
                   
                 (GYATTAGAAAATYAGYTATAAATG) wherein Z is 24; 
               
               
                   
                 and 
               
               
                   
                   
               
               
                   
                 e) 
               
            
           
           
               
            
               
                 SEQ ID NO: 75 
               
            
           
           
               
               
            
               
                   
                 (YYATYYGYTTGYATTAGAAAGTYAGY) wherein Z is 26; 
               
            
           
         
       
         
         
           
             wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 71 to 75 is thymine (T), and each Y of SEQ ID NOS: 71 to 75 is cytosine (C). 
           
         
       
    
     In various embodiments, the dystrophin targeting sequence comprises one of SEQ ID NOS: 76 to 3485, is selected from one of SEQ ID NOS: 76 to 3485, is a fragment of at least 10 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 76 to 3485, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 76 to 3485, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 76 to 3485 is thymine (T), and each Y of SEQ ID NOS: 76 to 3485 is cytosine (C). In some embodiments, a targeting sequence may comprise SEQ ID NO: 76. 
     In some embodiments, the antisense oligomer is a compound of formula (VII): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, where:
         each Nu is a nucleobase which taken together form a targeting sequence; and   Z is an integer from 8 to 48;   each Y is O;   each R 1  is independently selected from:       

     
       
         
         
             
             
         
       
         
         
           
             R 2  is selected from H, acyl, trityl, 4-methoxytrityl, C 1 -C 6  alkyl, —C(═NH)NH 2 , and —C(O)—R 23 ; and 
             R 3  is selected from an electron pair, H, and C 1 -C 6  alkyl. 
           
         
       
    
     In various embodiments, the targeting sequence is complementary to a target region within myostatin pre-mRNA. In some embodiments, the targeting sequence is complementary to 12 or more contiguous nucleotides in a target region entirely within an exon of myostatin pre-mRNA or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 1 to 3) of myostatin pre mRNA. 
     In various embodiments, the targeting sequence is complementary to a target region within dystrophin pre-mRNA. In some embodiments, the targeting sequence is complementary to 10 or more contiguous nucleotides in a target region within an exon of dystrophin pre-mRNA selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. In embodiments, the target region is entirely within an exon of dystrophin pre-mRNA where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 4 to 15) of dystrophin pre-mRNA. 
     In various embodiments, the myostatin targeting sequence comprises one of SEQ ID NOS: 16 to 75, is selected from one of SEQ ID NOS: 16 to 75, is a fragment of at least 12 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 16 to 75, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 16 to 75, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 16 to 75 is thymine (T), and each Y of SEQ ID NOS: 16 to 75 is cytosine (C).
         In some embodiments, the myostatin targeting sequence of formula (VII) is selected from:       

     
       
         
           
               
               
            
               
                   
                 a) 
               
            
           
           
               
            
               
                 SEQ ID NO: 71 
               
            
           
           
               
               
            
               
                   
                 (YYAGYYYAXYXXYXYYXGGXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 b) 
               
            
           
           
               
            
               
                 SEQ ID NO: 72 
               
            
           
           
               
               
            
               
                   
                 (YAYXXAYYAGYYYAXYXXYXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 c) 
               
            
           
           
               
            
               
                 SEQ ID NO: 73 
               
            
           
           
               
               
            
               
                   
                 (YYAYXXGYAXXAGAAAAXYAGY) wherein Z is 22; 
               
               
                   
                   
               
               
                   
                 d) 
               
            
           
           
               
            
               
                 SEQ ID NO: 74 
               
            
           
           
               
               
            
               
                   
                 (GYATTAGAAAATYAGYTATAAATG) wherein Z is 24; 
               
               
                   
                 and 
               
               
                   
                   
               
               
                   
                 e) 
               
            
           
           
               
            
               
                 SEQ ID NO: 75 
               
            
           
           
               
               
            
               
                   
                 (YYATYYGYTTGYATTAGAAAGTYAGY) wherein Z is 26; 
               
            
           
         
       
         
         
           
             wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 71 to 75 is thymine (T), and each Y of SEQ ID NOS: 71 to 75 is cytosine (C). 
           
         
       
    
     In various embodiments, the dystrophin targeting sequence comprises one of SEQ ID NOS: 76 to 3485, is selected from one of SEQ ID NOS: 76 to 3485, is a fragment of at least 10 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 76 to 3485, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 76 to 3485, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 76 to 3485 is thymine (T), and each Y of SEQ ID NOS: 76 to 3485 is cytosine (C). In some embodiments, a targeting sequence may comprise SEQ ID NO: 76. 
     In various embodiments, at least one X of the targeting sequence is T. In various embodiments, each X of the targeting sequence is T. 
     In various embodiments, at least one X of the targeting sequence is U. In various embodiments, each X of the targeting sequence is U. 
     In various embodiments, at least one Y of the targeting sequence is 5 mC. In various embodiments, each Y of the targeting sequence is 5 mC. 
     In various embodiments, at least one Y of the targeting sequence is C. In various embodiments, each Y of the targeting sequence is C. 
     In various embodiments, at least one X of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is T. In various embodiments, each X of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is T. 
     In various embodiments, at least one X of the targeting sequence is U. In various embodiments, each X of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is U. 
     In various embodiments, at least one Y of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is 5 mC. In various embodiments, each Y of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is 5 mC. 
     In various embodiments, at least one Y of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is C. In various embodiments, each Y of SEQ ID NOS: 16 to 75 and SEQ ID NO: 76 to 3485 is C. 
     In certain embodiments, the antisense oligomer is a compound of formula (VIII): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, where:
         each Nu is a nucleobase which taken together form a targeting sequence; and   is an integer from 8 to 48.       

     In various embodiments, the targeting sequence is complementary to a target region within myostatin pre-mRNA. In some embodiments, the targeting sequence is complementary to 12 or more contiguous nucleotides in a target region within an exon/intron splice junction site, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 1 to 3) of myostatin pre mRNA. 
     In various embodiments, the targeting sequence is complementary to a target region within dystrophin pre-mRNA. In some embodiments, the targeting sequence is complementary to 10 or more contiguous nucleotides in a target region within an exon of dystrophin pre-mRNA selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. In embodiments, the target region is entirely within an exon of dystrophin pre-mRNA where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 4 to 15) of dystrophin pre-mRNA. 
     In various embodiments, the myostatin targeting sequence comprises one of SEQ ID NOS: 16 to 75, is selected from one of SEQ ID NOS: 16 to 75, is a fragment of at least 12 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 16 to 75, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 16 to 75, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 16 to 75 is thymine (T), and each Y of SEQ ID NOS: 16 to 75 is cytosine (C). 
     In some embodiments, the myostatin targeting sequence is selected from: 
     
       
         
           
               
               
            
               
                   
                 a) 
               
            
           
           
               
            
               
                 SEQ ID NO: 71 
               
            
           
           
               
               
            
               
                   
                 (YYAGYYYAXYXXYXYYXGGXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 b) 
               
            
           
           
               
            
               
                 SEQ ID NO: 72 
               
            
           
           
               
               
            
               
                   
                 (YAYXXAYYAGYYYAXYXXYXYYXGG) wherein Z is 25; 
               
               
                   
                   
               
               
                   
                 c) 
               
            
           
           
               
            
               
                 SEQ ID NO: 73 
               
            
           
           
               
               
            
               
                   
                 (YYAYXXGYAXXAGAAAAXYAGY) wherein Z is 22; 
               
               
                   
                   
               
               
                   
                 d) 
               
            
           
           
               
            
               
                 SEQ ID NO: 74 
               
            
           
           
               
               
            
               
                   
                 (GYATTAGAAAATYAGYTATAAATG) wherein Z is 24; 
               
               
                   
                 and 
               
               
                   
                   
               
               
                   
                 e) 
               
            
           
           
               
            
               
                 SEQ ID NO: 75 
               
            
           
           
               
               
            
               
                   
                 (YYATYYGYTTGYATTAGAAAGTYAGY) wherein Z is 26; 
               
            
           
         
       
         
         
           
             wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 71 to 75 is thymine (T), and each Y of SEQ ID NOS: 71 to 75 is cytosine (C). 
           
         
       
    
     In various embodiments, the dystrophin targeting sequence comprises one of SEQ ID NOS: 76 to 3485, is selected from one of SEQ ID NOS: 76 to 3485, is a fragment of at least 10 contiguous nucleotides of a sequence selected from at least one of SEQ ID NOS: 76 to 3485, or is a variant having at least 90% sequence identity to a sequence selected from at least one of SEQ ID NOS: 76 to 3485, wherein each X is independently selected from uracil (U) or thymine (T), and wherein each Y is independently selected from cytosine (C) or 5-Methylcytosine (5 mC). In some embodiments, each X of SEQ ID NOS: 76 to 3485 is thymine (T), and each Y of SEQ ID NOS: 76 to 3485 is cytosine (C). In some embodiments, a targeting sequence may comprise SEQ ID NO: 76. 
     In some embodiments, each Nu of the antisense oligomers of the disclosure, including compounds of formula (I), (IV), (V), (VI), (VII) and (VIII), is independently selected from adenine, guanine, thymine, uracil, cytosine, hypoxanthine (inosine), 2,6-diaminopurine, 5-methyl cytosine, C5-propynyl-modified pyrimidines, and 10-(9-(aminoethoxy)phenoxazinyl). In some embodiments, the targeting sequence of the antisense oligomers of the disclosure, including compounds of formula (I), (IV), (V), (VI), (VII) and (VIII), comprises a sequence selected from SEQ ID NOS: 2, 3, 4 or 6, is selected from SEQ ID NOS: 2, 3, 4 or 6, is a fragment of at least 12 contiguous nucleotides of a sequence selected from SEQ ID NOS: 2, 3, 4 or 6, or is a variant having at least 90% sequence identity to a sequence selected from SEQ ID NOS: 2, 3, 4 or 6, where X is selected from uracil (U) or thymine (T), and wherein I is inosine. 
     Additional modified antisense oligomers/chemistries that can be used in accordance with the present disclosure include those described in the following patents and patent publications, which are hereby incorporated by reference in their entirety: PCT Publication Nos. WO 2007/002390; WO 2010/120820; and WO 2010/148249; U.S. Pat. No. 7,838,657; and U.S. Patent Application No. 2011/0269820. 
     C. The Preparation of Morpholino Subunits and Phosphoramidate Internucleoside Linkers 
     Morpholino monomer subunits, the modified internucleoside linkages, and oligomers comprising the same can be prepared as described, for example, in U.S. Pat. Nos. 5,185,444, and 7,943,762, which are hereby incorporated by reference in their entirety. The morpholino subunits can be prepared according to the following general Reaction Scheme I. 
     
       
         
         
             
             
         
       
     
     Referring to Reaction Scheme 1, where B represents a base pairing moiety and PG represents a protecting group, the morpholino subunits may be prepared from the corresponding ribonucleoside (1) as shown. The morpholino subunit (2) may be optionally protected by reaction with a suitable protecting group precursor, for example trityl chloride. The 3′ protecting group is generally removed during solid-state oligomer synthesis as described in more detail below. The base pairing moiety may be suitably protected for sold phase oligomer synthesis. Suitable protecting groups include benzoyl for adenine and cytosine, phenylacetyl for guanine, and pivaloyloxymethyl for hypoxanthine (I). The pivaloyloxymethyl group can be introduced onto the N 1  position of the hypoxanthine heterocyclic base. Although an unprotected hypoxanthine subunit, may be employed, yields in activation reactions are far superior when the base is protected. Other suitable protecting groups include those disclosed in U.S. Pat. No. 8,076,476, which is hereby incorporated by reference in its entirety. 
     Reaction of compound 3 with the activated phosphorous compound 4, results in morpholino subunits having the desired linkage moiety compound 5. Compounds of structure 4 can be prepared using any number of methods known to those of skill in the art. For example, such compounds may be prepared by reaction of the corresponding amine and phosphorous oxychloride. In this regard, the amine starting material can be prepared using any method known in the art, for example those methods described in the Examples and in U.S. Pat. Nos. 5,185,444, 7,943,762, and 8,779,128, which are hereby incorporated by reference in its entirety. 
     Compounds of structure 5 can be used in solid-phase automated oligomer synthesis for preparation of oligomers comprising the internucleoside linkages. Such methods are well known in the art. Briefly, a compound of structure 5 may be modified at the 5′ end to contain a linker to a solid support. For example, compound 5 may be linked to a solid support by a linker comprising L11 and L15. Once supported, the protecting group (e.g., trityl) is removed and the free amine is reacted with an activated phosphorous moiety of a second compound of structure 5. This sequence is repeated until the desired length of oligo is obtained. The protecting group in the terminal 5′ end may either be removed or left on if a 5′-modification is desired. The oligo can be removed from the solid support using any number of methods, for example treatment with DTT followed by ammonium hydroxide. 
     The preparation of modified morpholino subunits and morpholino-based oligomers are described in more detail in the Examples. The morpholino-based oligomers containing any number of modified linkages may be prepared using methods described herein, methods known in the art and/or described by reference herein. Also described in the examples are global modifications of morpholino-based oligomers prepared as previously described (see e.g., PCT Publication No. WO 2008/036127, which is hereby incorporated by reference in its entirety). 
     The term “protecting group” refers to chemical moieties that block some or all reactive moieties of a compound and prevent such moieties from participating in chemical reactions until the protective group is removed, for example, those moieties listed and described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd ed. John Wiley &amp; Sons (1999), which is hereby incorporated by reference in its entirety. It may be advantageous, where different protecting groups are employed, that each (different) protective group be removable by a different means. Protective groups that are cleaved under totally disparate reaction conditions allow differential removal of such protecting groups. For example, protective groups can be removed by acid, base, and hydrogenolysis. Groups such as trityl, dimethoxytrityl, acetal and tert-butyldimethylsilyl are acid labile and may be used to protect carboxy and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups, which are removable by hydrogenolysis, and Fmoc groups, which are base labile. Carboxylic acid moieties may be blocked with base labile groups such as, without limitation, methyl, or ethyl, and hydroxy reactive moieties may be blocked with base labile groups such as acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are both acid and base stable but hydrolytically removable. 
     Carboxylic acid and hydroxyl reactive moieties may also be blocked with hydrolytically removable protective groups such as the benzyl group, while amine groups may be blocked with base labile groups such as Fmoc. A particularly useful amine protecting group for the synthesis of compounds of Formula (I) is the trifluoroacetamide. Carboxylic acid reactive moieties may be blocked with oxidatively-removable protective groups such as 2,4-dimethoxybenzyl, while co-existing amino groups may be blocked with fluoride labile silyl carbamates. 
     Allyl blocking groups are useful in the presence of acid- and base-protecting groups since the former are stable and can be subsequently removed by metal or pi-acid catalysts. For example, an allyl-blocked carboxylic acid can be deprotected with a palladium(0)-catalyzed reaction in the presence of acid labile t-butyl carbamate or base-labile acetate amine protecting groups. Yet another form of protecting group is a resin to which a compound or intermediate may be attached. As long as the residue is attached to the resin, that functional group is blocked and cannot react. Once released from the resin, the functional group is available to react.
         Typical blocking/protecting groups are known in the art and include, but are not limited to the following moieties:       

     
       
         
         
             
             
         
       
     
     Unless otherwise noted, all chemicals were obtained from Sigma-Aldrich-Fluka (St. Louis, Mo.). Benzoyl adenosine, benzoyl cytidine, and phenylacetyl guanosine were obtained from Carbosynth Limited (Berkshire, UK). 
     Synthesis of PMO, PMOplus, PPMO, and PMO-X containing further linkage modifications as described herein was done using methods known in the art and described in pending U.S. patent application Ser. Nos. 12/271,036 and 12/271,040 and PCT Publication No. WO 2009/064471, which is hereby incorporated by reference in its entirety. 
     PMO with a 3′ trityl modification are synthesized essentially as described in PCT Publication No. WO 2009/064471 with the exception that the detritylation step is omitted. 
     D. Cell-Penetrating Peptides 
     The modified antisense oligomer compounds of the disclosure may be conjugated to a peptide, also referred to herein as a cell penetrating peptide (CPP). In certain preferred embodiments, the peptide is an arginine-rich peptide transport moiety effective to enhance transport of the compound into cells. The transport moiety is preferably attached to a terminus of the oligomer. The peptides have the capability of inducing cell penetration within 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100% of cells of a given cell culture population, including all integers in between, and allow macromolecular translocation within multiple tissues in vivo upon systemic administration. In one embodiment, the cell-penetrating peptide may be an arginine-rich peptide transporter. In another embodiment, the cell-penetrating peptide may be Penetratin or the Tat peptide. These peptides are well known in the art and are disclosed, for example, in US Publication No. 2010-0016215 A1, which is hereby incorporated by reference in its entirety. One approach to conjugation of peptides to modified antisense oligomers of the disclosure can be found in PCT publication WO2012/150960, which is hereby incorporated by reference in its entirety. Some embodiments of a peptide conjugated oligomer of the present disclosure utilize glycine as the linker between the CPP and the modified antisense oligomer. For example, a peptide conjugated PMO of the disclosure consists of R 6 -G-PMO. 
     The transport moieties as described above have been shown to greatly enhance cell entry of attached oligomers, relative to uptake of the oligomer in the absence of the attached transport moiety. Uptake is preferably enhanced at least ten fold, and more preferably twenty fold, relative to the unconjugated compound. 
     The use of arginine-rich peptide transporters (i.e., cell-penetrating peptides) are particularly useful in practicing the present disclosure. Certain peptide transporters have been shown to be highly effective at delivery of antisense compounds into primary cells including muscle cells (Marshall, Oda et al. 2007; Jearawiriyapaisarn, Moulton et al. 2008; Wu, Moulton et al. 2008, which are hereby incroporated by reference in their entirety). Furthermore, compared to other known peptide transporters such as Penetratin and the Tat peptide, the peptide transporters described herein, when conjugated to an antisense PMO, demonstrate an enhanced ability to alter splicing of several gene transcripts (Marshall, Oda et al. 2007, which is hereby incorporated by reference in its entirety). 
     Exemplary peptide transporters, excluding linkers are given below in Table 5. 
     
       
         
           
               
             
               
                 TABLE 5 
               
             
            
               
                   
               
               
                 Exemplary peptide transporters 
               
            
           
           
               
               
               
            
               
                   
                   
                 CPP SEQ 
               
               
                 NAME (DESIGNATION) 
                 SEQUENCE 
                 ID NO A   
               
               
                   
               
               
                 rTAT 
                 rrrqrrkkr 
                 3486 
               
               
                   
               
               
                 Tat 
                 rkkrrqrrr 
                 3487 
               
               
                   
               
               
                 R 9 F 2   
                 rrrrrrrrrff 
                 3488 
               
               
                   
               
               
                 R 5 F 2 R 4   
                 rrrrrffrrrr 
                 3489 
               
               
                   
               
               
                 R 4   
                 rrrr 
                 3490 
               
               
                   
               
               
                 R 5   
                 rrrrr 
                 3491 
               
               
                   
               
               
                 R 6   
                 rrrrrr 
                 3492 
               
               
                   
               
               
                 R 7   
                 rrrrrrr 
                 3493 
               
               
                   
               
               
                 R 8   
                 rrrrrrrr 
                 3494 
               
               
                   
               
               
                 R 9   
                 rrrrrrrrr 
                 3495 
               
               
                   
               
               
                 (RX) 8   
                 rahxrahxrahxrahxrahxrahxrahxrahx 
                 3496 
               
               
                   
               
               
                 (RAhxR) 4 ; (P007) 
                 rahxrrahxrrahxrrahxr 
                 3497 
               
               
                   
               
               
                 (RAhxR) 5 ; (CP04057) 
                 rahxrrahxrrahxrrahxrrahxr 
                 3498 
               
               
                   
               
               
                 (RAhxRRBR) 2 ; (CP06062) 
                 rahxrrbrrahxrrbr 
                 3499 
               
               
                   
               
               
                 (RAR) 4 F 2   
                 rarrarrarrarff 
                 3500 
               
               
                   
               
               
                 (RGR) 4 F 2   
                 rgrrgrrgrrgrff 
                 3501 
               
               
                   
               
               
                   A Sequences assigned to CPP SEQ ID NOS do not include the linkage portion (e.g., C (cys), G (gly), P (pro), Ahx, B, AhxB where Ahx and B refer to 6-aminohexanoic acid and beta-alanine, respectively). 
               
            
           
         
       
     
     In various embodiments, G (as recited in formulas I, IV, and V) is a cell penetrating peptide (“CPP”) and linker moiety selected from —C(O)(CH 2 ) 5 NH—CPP, —C(O)(CH 2 ) 2 NH—CPP, —C(O)(CH 2 ) 2 NHC(O)(CH 2 ) 5 NH—CPP, and —C(O)CH 2 NH—CPP, or G is of the formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein the CPP is attached to the linker moiety by an amide bond at the CPP carboxy terminus. In some embodiments, the CPP is selected from SEQ ID NOS: 3486 to 3501. 
           
         
       
    
     In some embodiments, G (as recited in formulas I, IV, and V) is of the formula: 
     
       
         
         
             
             
         
       
         
         
           
             wherein R a  is selected from H, acetyl, benzoyl, and stearoyl, and J is an integer from 4 to 9. In certain embodiments J is 6. 
             In some embodiments, the CPP (as recited in formulas I, IV, and V) is of the formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             wherein R a  is selected from H, acetyl, benzoyl, and stearoyl, and J is an integer from 4 to 9. In certain embodiments, the CPP is SEQ ID NO: 15. In various embodiments, J is 6. In some embodiments R a  is selected from H and acetyl. For example, in some embodiments, R a  is H. In certain embodiments, R a  is acetyl. 
           
         
       
    
     IV. FORMULATIONS 
     The compounds of the disclosure 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, which are hereby incorporated by reference in their entirety. 
     The antisense compounds of the disclosure 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 disclosure, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. 
     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 oligomers of the disclosure are prepared as SATE [(S-acetyl-2-thioethyl) phosphate] derivatives according to the methods disclosed in PCT Publication No. WO 1993/24510 to Gosselin et al., published Dec. 9, 1993 or in PCT Publication No. WO 1994/26764 and U.S. Pat. No. 5,770,713 to Imbach et al., which are hereby incorporated by reference in their entirety. 
     The term “pharmaceutically acceptable salts” refers to physiologically and pharmaceutically acceptable salts of the compounds of the disclosure: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto. For oligomers, examples of pharmaceutically acceptable salts and their uses are further described in U.S. Pat. No. 6,287,860, which is hereby incorporated by reference in its entirety. 
     The present disclosure also includes pharmaceutical compositions and formulations which include the antisense compounds of the disclosure. The pharmaceutical compositions of the present disclosure 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. Oligomers with at least one 2′-O-methoxyethyl modification are believed to be particularly useful for oral administration. 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. 
     The pharmaceutical formulations of the present disclosure, 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. 
     The compositions of the present disclosure 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 disclosure 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. 
     Pharmaceutical compositions of the present disclosure include, but are not limited to, solutions, emulsions, foams and liposome-containing formulations. The pharmaceutical compositions and formulations of the present disclosure may comprise one or more penetration enhancers, carriers, excipients or other active or inactive ingredients. 
     Emulsions are typically heterogeneous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 μm in diameter. 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. Microemulsions are included as an embodiment of the present disclosure. Emulsions and their uses are well known in the art and are further described in U.S. Pat. No. 6,287,860, which is hereby incorporated by reference in its entirety. 
     Formulations of the present disclosure include liposomal formulations. As used in the present disclosure, the term “liposome” means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers. Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior that contains the composition to be delivered. Cationic liposomes are positively charged liposomes which are believed to interact with negatively charged DNA molecules to form a stable complex. Liposomes that are pH-sensitive or negatively-charged are believed to entrap DNA rather than complex with it. Both cationic and noncationic liposomes have been used to deliver DNA to cells. 
     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 comprises one or more glycolipids or is derivatized with one or more hydrophilic oligomers, such as a polyethylene glycol (PEG) moiety. Liposomes and their uses are further described in U.S. Pat. No. 6,287,860, which is hereby incorporated by reference in its entirety. 
     The pharmaceutical formulations and compositions of the present disclosure may also include surfactants. The use of surfactants in drug products, formulations and in emulsions is well known in the art. Surfactants and their uses are further described in U.S. Pat. No. 6,287,860, which is hereby incorporated by reference in its entirety. 
     In some embodiments, the present disclosure employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly oligomers. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs. 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. Penetration enhancers and their uses are further described in U.S. Pat. No. 6,287,860, which is hereby incorporated by reference in its entirety. 
     One of skill in the art will recognize that formulations are routinely designed according to their intended use, i.e. route of administration. 
     Formulations for topical administration include those in which the oligomers of the disclosure are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. 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). 
     For topical or other administration, therapeutics including oligomers of the disclosure may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, therapeutics may be complexed to lipids, in particular to cationic lipids. Fatty acids and esters, pharmaceutically acceptable salts thereof, and their uses are further described in U.S. Pat. No. 6,287,860, which is hereby incorporated by reference in its entirety. Topical formulations are described in detail in U.S. patent application Ser. No. 09/315,298 filed on May 20, 1999 and Mourich et al., 2009, J. Invest. Dermatol., 129(8):1945-53, which are hereby incorporated by reference in their entirety. 
     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. Oral formulations are those in which oligomers of the disclosure are administered in conjunction with one or more penetration enhancers surfactants and chelators. Surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Bile acids/salts and fatty acids and their uses are further described in U.S. Pat. No. 6,287,860, which is hereby incorporated by reference in its entirety. In some embodiments, the present disclosure provides combinations of penetration enhancers, for example, fatty acids/salts in combination with bile acids/salts. An exemplary combination is the sodium salt of lauric acid, capric acid and UDCA. Further penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. Oligomers of the disclosure may be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. Oligomer complexing agents and their uses are further described in U.S. Pat. No. 6,287,860, which is hereby incorporated by reference in its entirety. Oral formulations for oligomers and their preparation are described in detail in U.S. patent application Ser. No. 09/108,673 (filed Jul. 1, 1998), Ser. No. 09/315,298 (filed May 20, 1999) and Ser. No. 10/071,822 (filed Feb. 8, 2002), which are hereby incorporated by reference in their entirety. 
     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. 
     In another related embodiment, compositions of the disclosure may contain one or more antisense compounds, particularly oligomers, targeted to a first nucleic acid and one or more additional antisense compounds targeted to a second nucleic acid target. Alternatively, compositions of the disclosure may contain two or more antisense compounds targeted to different regions of the same nucleic acid target. Numerous examples of antisense compounds are known in the art. Two or more combined compounds may be used together or sequentially. 
     V. METHODS OF USE 
     Certain aspects relate to methods of treating a subject having Duchenne muscular dystrophy or a related disorder comprising administering a dustrophin therapeutic to a subject also receiving a myostatin therapeutic. 
     In aspects, a therapeutic is administered to a subject having DMD or a related disorder. In embodiments, one or more therapeutic may be administered to the subject prior to treatment with a modified antisense oligomer as described herein. In embodiments, one or more therapeutic may be administered to the subject prior to, simultaneously or after administration of a modified antisense oligomer. In embodiments, a therapeutic is a protein or nucleic acid. In some embodiments, a protein is an antibody or a soluble receptor. In embodiments, a soluble receptor is ACVR2. In embodiments, a nucleic acid is an antisense oligomer or a siRNA. In some embodiments, an antisense oligomer is a modified antisense oligomer as described herein. 
     In embodiments, a therapeutic is a myostatin therapeutic capable of suppressing one or both of myostatin activity or myostatin expression in a subject. A myostatin therapeutic may be a therapeutic that targets myostatin pre-mRNA and interferes with transcription of the myostatin pre-mRNA to mature mRNA. In embodiments, a myostatin therapeutic is capable of inducing exon skipping during the processing of human myostatin pre-mRNA. In embodiments, a myostatin therapeutic induces skipping of exon 2 in myostatin pre-mRNA and inhibits the expression of exon 2 containing myostatin pre-mRNA. A myostatin therapeutic may be a therapeutic that targets myostatin protein and interferes with the myostatin protein binding with the myostatin receptor. 
     A myostatin therapeutic is selected from a protein and a nucleic acid. A protein may be an anti-myostatin antibody, for example anti-GDF8 (Abcam, Cambridge Mass.) or a soluble receptor. In embodiments, a soluble receptor is ACVR2. A nucleic acid is selected from an antisense oligomer and a siRNA. An antisense oligomer may be a modified myostatin antisense oligomer as described herein. 
     In embodiments, a therapeutic is a dystrophin therapeutic capable of increasing dystrophin in a subject. A dystrophin therapeutic may increase the expression of dystrophin or a truncated form of dystrophin that is functional or semi-functional. A truncated form of dystrophin includes, but is not limited to, micro-dystrophin and mini-dystrophin (disclosed in EP Patent no. 2125006, which is hereby incorporated by reference in its entirety). A dystrophin therapeutic may be a therapeutic that targets dystrophin pre-mRNA and modulates the transcription of the dystrophin pre-mRNA to mature mRNA. In embodiments, a dystrophin therapeutic is capable of inducing exon skipping during processing of human dystrophin pre-mRNA. In embodiments, a targeted dystrophin pre-mRNA has one or more genetic mutations. A dystrophin therapeutic induces exon skipping such that one or more exons containing one or more genetic mutations are removed from the dystrophin pre-mRNA during processing to mature mRNA. The resulting truncated mRNA is capable of translation into a functional or semi-functional dystrophin protein. 
     In some aspects, a modified dystrophin antisense oligomer comprises a nucleotide sequence of sufficient length and complementarity to specifically hybridize to a region within the pre-mRNA of the dystrophin gene, wherein binding of the modified antisense oligomer to the region induces exon skipping during processing of dystrophin pre-mRNA. In embodiments, exon skipping during processing of dystrophin pre-mRNA results in the removal of one or more exons having a genetic mutation from the pre-mRNA. In embodiments, the removal of one or more exons having a genetic mutation from the dystrophin pre-mRNA increases the level of non-mutated dystrophin pre-mRNA in a cell and/or tissue of the subject. The increase in the level of non-mutated dystrophin pre-mRNA in the subject may further translate to increased expression of functional or semi-functional dystrophin protein. Thus, the present disclosure relates to methods of increasing functional or semi-functional dystrophin protein by increasing the level of non-mutated dystrophin mRNA using the modified dystrophin antisense oligomers as described herein. 
     In some aspects, a modified myostatin antisense oligomer comprises a nucleotide sequence of sufficient length and complementarity to specifically hybridize to a region within the pre-mRNA of the myostatin gene, wherein binding of the modified antisense oligomer to the region induces exon skipping during processing of myostatin pre-mRNA. In embodiments, binding of the modified myostatin oligomer to the region decreases the level of exon 2-containing myostatin mRNA in a cell and/or tissue of the subject. The decrease in the level of exon 2-containing myostatin mRNA in the subject may further translate to decreased expression of functional myostatin protein. 
     Methods also include treating an individual afflicted with or at risk for developing Duchenne muscular dystrophy (DMD) or a related disorder, comprising administering an effective amount of a modified antisense oligomer of the disclosure to the subject in combination with a therapeutic agent. The modified antisense oligomer may or may not be in the same composition and may or may not be co-administered to a subject. In various embodiments, the modified antisense oligomer is administered at or near the same time as the therapeutic agent. In further embodiments, the modified antisense oligomer is administered at a substantially different time as the therapeutic agent. Exemplary sequences targeted by the modified antisense oligomers as described herein are shown in Tables 1 and 2. 
     Also included are therapeutics and modified antisense oligomers for treating DMD or related disorders or for use in the preparation of a medicament for the treatment of DMD or related disorders, the treatment or the medicament comprising a therapeutic. In embodiments, a medicament includes a modified antisense oligomer as described herein, e.g., where the modified antisense oligomer comprises 10 to 50 subunits, optionally having at least one subunit that is a nucleotide analog having (i) a modified internucleoside linkage, (ii) a modified sugar moiety, or (iii) a combination of the foregoing; and a targeting sequence complementary to 10 or more contiguous nucleotides in a target region within dystrophin or myostatin pre-mRNA. 
     In various embodiments, the targeting sequence is complementary to a target region within myostatin pre-mRNA. In some embodiments, the targeting sequence is complementary to 12 or more contiguous nucleotides in a target region entirely within exon 2 where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 1 to 3) of myostatin pre-mRNA. In some embodiments, the targeting sequence of the modified antisense oligomers (a) comprises a sequence selected from SEQ ID NOS: 16-75, (b) is selected from SEQ ID NOS: 16-75, (c) is a fragment of at least 12 contiguous nucleotides of a sequence selected from SEQ ID NOS: 16-75, or (d) is a variant having at least 90% sequence identity to a sequence selected from SEQ ID NOS: 16-75, where X is selected from uracil (U) or thymine (T), and C is selected from cytosine (C) or 5-methylcytosine (5 mC). 
     In various embodiments, the targeting sequence is complementary to a target region within dystrophin pre-mRNA. In some embodiments, the targeting sequence is complementary to 10 or more contiguous nucleotides in a target region within an exon of dystrophin pre-mRNA selected from exon 7, exon 8, exon 9, exon 19, exon 23, exon 44, exon 45, exon 50, exon 51, exon 52, exon 53, or exon 55. In embodiments, the target region is entirely within an exon of dystrophin pre-mRNA where no part of the targeting sequence spans a splice junction, or a region spanning an intron/exon or exon/intron splice junction (e.g., SEQ ID NOS: 4 to 15) of dystrophin pre-mRNA. In some embodiments, the targeting sequence of the modified antisense oligomers (a) comprises a sequence selected from SEQ ID NOS: 76-3485, (b) is selected from SEQ ID NOS: 76-3485, (c) is a fragment of at least 10 contiguous nucleotides of a sequence selected from SEQ ID NOS: 76-3485, or (d) is a variant having at least 90% sequence identity to a sequence selected from SEQ ID NOS: 76-3485, where X is selected from uracil (U) or thymine (T), and C is selected from cytosine (C) or 5-methylcytosine (5 mC). 
     In some embodiments, the methods of treating DMD or related disorders or the medicaments for the treatment of DMD or related disorders include modified antisense oligomers having a nucleotide analog subunit comprising a modified sugar moiety. The modified sugar moiety may be selected from a peptide nucleic acid (PNA) subunit, a locked nucleic acid (LNA) subunit, a 2′O,4′C-ethylene-bridged nucleic acid (ENA) subunit, a tricyclo-DNA (tc-DNA) subunit, a 2′ O-methyl subunit, a 2′ O-methoxyethyl subunit, a 2′-fluoro subunit, a 2′-O-[2-(N-methylcarbamoyl)ethyl]subunit, and a morpholino subunit. 
     These additional aspects and embodiments include modified antisense oligomers having a nucleotide analog subunit comprising a modified internucleoside linkage. In various embodiments, the modified internucleoside linkage is selected from a phosphorothioate internucleoside linkage, a phosphoramidate internucleoside linkage, a phosphorodiamidate internucleoside linkage. In further embodiments, the phosphorodiamidate internucleoside linkage comprises a phosphorous atom that is covalently bonded to a (1,4-piperazin)-1-yl moiety, a substituted (1,4-piperazin)-1-yl moiety, a 4-aminopiperidin-1-yl moiety, or a substituted 4-aminopiperidin-1-yl moiety. 
     These additional aspects and embodiments include modified antisense oligomers having a nucleotide analog subunit comprising at least one combination of a modified sugar moiety and a modified internucleoside linkage. 
     In some embodiments, the modified antisense oligomer is actively taken up by mammalian cells. In further embodiments, the modified antisense oligomer may be conjugated to a transport moiety (e.g., transport peptide or CPP) as described herein to facilitate such uptake. Various aspects relate to methods of decreasing the expression of exon 2-containing myostatin mRNA transcript and/or functional myostatin protein in a cell, tissue, and/or subject, using the modified antisense oligomers as described herein. In some instances, exon 2-containing myostatin mRNA transcript and/or functional myostatin protein is decreased or reduced by about or at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control, for example, a control cell/subject (for example, a subject not having Duchenne muscular dystrophy or a related disorder), a control composition without the modified antisense oligomer, the absence of treatment, and/or an earlier time-point. Also included are methods of decreasing the expression of exon 2-containing mRNA transcript or functional myostatin protein relative to the levels of a healthy control, for example, a subject not having Duchenne muscular dystrophy or a related disorder. As used herein, an “effective amount” or “therapeutic amount” refers to the dose(s) of the modified antisense oligomers that is capable to bind to the target region of myostatin pre-mRNA transcript and to decrease the expression of exon 2-containing myostatin mRNA transcript and functional myostatin protein in the range of the percentages disclosed with regard to the increase when administered to a subject, as compared to a control cell/subject. 
     Various aspects relate to methods for modulating the splicing of intron and exons of dystrophin pre-mRNA and increasing the expression of dystrophin or truncated dystrophin pre-mRNA in a cell, tissue, and/or subject, using the modified antisense oligomers as described herein. In further aspects, expression of a truncated form of dystrophin pre-mRNA is enhanced, such as relative to full length wildtype dystrophin pre-mRNA. In some instances, dystrophin mRNA transcript and/or functional or semi-functional dystrophin protein is increased or enhanced by about or at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control, for example, a control cell/subject (for example, a subject not having Duchenne muscular dystrophy or a related disorder), a control composition without the modified antisense oligomer, the absence of treatment, and/or an earlier time-point. The methods also include increasing the expression of dystrophin mRNA transcript or functional or semi-functional dystrophin protein relative to the levels of a healthy control, for example, a subject not having Duchenne muscular dystrophy or a related disorder. As used herein, an “effective amount” or “therapeutic amount” refers to the dose(s) of the modified antisense oligomers that is capable to bind to a target region of dystrophin pre-mRNA transcript and to increase the expression of dystrophin or truncated dystrophin mRNA transcript and functional dystrophin protein in the range of the percentages disclosed with regard to the increase when administered to a subject, as compared to a control cell/subject. 
     The methods also include decreasing expression of a functional/active myostatin protein in a cell, tissue, and/or subject, as described herein. In certain instances, the level of functional/active myostatin protein is decreased by about or at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control, for example, a control cell/subject (for example, a subject having Duchenne muscular dystrophy or a related disorder), a control composition without the therapeutic, the absence of treatment, and/or an earlier time-point. The methods also include decreasing the expression of functional/active myostatin protein relative to the levels of an affected control, for example, a subject having Duchenne muscular dystrophy or a related disorder. 
     The methods also include increasing expression of a functional or semi-functional/active dystrophin protein in a cell, tissue, and/or subject, as described herein. In certain instances, the level of functional or semi-functional/active dystrophin protein is increased by about or at least about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% relative to a control, for example, a control cell/subject (for example, a subject not having Duchenne muscular dystrophy or a related disorder), a control composition without the therapeutic, the absence of treatment, and/or an earlier time-point. The methods also include increasing the expression of functional or semi-functional/active dystrophin protein relative to the levels of an affected control, for example, a subject having Duchenne muscular dystrophy or a related disorder. 
     The methods also include inhibiting the progression of Duchenne muscular dystrophy and related disorders in a subject using the therapeutics in combination with an antisense oligomer as described herein. 
     In some embodiments, the therapeutic and modified antisense oligomer are administered to a subject exhibiting one or more symptoms of DMD or a related disorder, in one or more suitable pharmaceutical carriers. As used herein, the term “treat” refers to an amelioration of DMD or a related disorder, or at least one discernible symptom related to DMD or a related disorder. In some embodiments, “treat” refers to an amelioration of at least one measurable physical and/or biological parameter that is not necessarily discernible by the subject. The subject may experience, for example, physical improvement of muscle strength and coordination. Those parameters may be assessed by e.g., self-evalulation tests, physician&#39;s examinations, lab tests for physical and physiological measurements, and biological tests of samples from the subject. In another embodiment, “treat” refers to slowing the progression or reversing the progression of DMD or a related disorder. As used herein, “prevent” or “inhibit” refers to delaying the onset or reducing the risk of developing DMD or a related disorder. 
     The methods include reducing, or improving, as appropriate, one or more symptoms of DMD and related disorders in a subject in need thereof. Particular examples include symptoms of progressive muscle weakness such as frequent falls, difficulty getting up from a lying or sitting position, trouble running and jumping, waddling gait, walking on the toes, large calf muscles, muscle pain and stiffness and learning disabilities. 
     The methods also include increasing skeletal muscle mass in a subject. The methods also include treating or preventing the decrease of muscle mass in a subject, in a healthy subject or a subject afflicted with a disease, disorder or condition. The methods also include treating skeletal muscle mass deficiency in a subject afflicted with a disease, disorder, or condition. In various embodiments, blood or tissue levels of one or both of myostatin and dystrophin protein are measured in a patient prior to administration of one or both of a therapeutic agent and an antisense oligomer described herein. An effective amount of one or both of a therapeutic agent and an antisense oligomer herein is administered to the subject. Blood or tissue levels of one or both of myostatin and dystrophin protein are measured in the subject after a select time and administration of the antisense oligomer. Optionally, the dosage and/or dosing schedule of one or both of a therapeutic agent and an antisense oligomer is adjusted according to the measurement, for example, to increase the dosage to ensure a therapeutic amount of one or both is present in the subject. A select time may include an amount of time after administration of one or both of a therapeutic agent and an antisense oligomer described herein, to allow time for absorption into the bloodstream and/or metabolization by the liver and other metabolic processes. In some embodiments, a select time may be about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, 20, 22, or 24 hours after administration. In some embodiments, a select time may be about 12, 18 or 24 hours after administration. In other embodiments, a select time may be about 1, 2, 3, 4, 5, 6 or 7 days after administration. 
     In conjunction with such treatment, pharmacogenomics (i.e., the study of the relationship between an individual&#39;s genotype and that individual&#39;s response to a foreign compound or drug) may be considered. Differences in metabolism of therapeutics can lead to severe toxicity or therapeutic failure by altering the relation between dose and blood concentration of the pharmacologically active drug. Thus, a physician or clinician may consider applying knowledge obtained in relevant pharmacogenomics studies in determining whether to administer a therapeutic agent as well as tailoring the dosage and/or therapeutic regimen of treatment with a therapeutic agent. 
     Effective administration and delivery of the therapeutic agent including a modified antisense oligomer to the target nucleic acid is a further aspect. Routes of therapeutic agent delivery include, but are not limited to, various systemic routes, including oral and parenteral routes, e.g., intravenous, subcutaneous, intraperitoneal, and intramuscular, as well as inhalation, transdermal and topical delivery. The appropriate route may be determined by one of skill in the art, as appropriate to the condition of the subject under treatment. Vascular or extravascular circulation, the blood or lymph system, and the cerebrospinal fluid are some non-limiting sites where the RNA may be introduced. 
     In particular embodiments, the therapeutic agent(s) are administered to the subject by intravenous (IV) or subcutaneous (SC), i.e., they are administered or delivered intravenously into a vein or subcutaneously into the fat layer between the skin and muscle. Non-limiting examples of intravenous injection sites include a vein of the arm, hand, leg, or foot. Non-limiting examples of subcutaneous injections sites include the abdomen, thigh, lower back or upper arm. In exemplary embodiments, a PMO, PMO-X, or PPMO forms of the modified antisense oligomer is administered by IV or SC. In other embodiments, the modified antisense oligomer(s) are administered to the subject by intramuscular (IM), e.g., they are administered or delivered intramuscularly into the deltoid muscle of the arm, the vastus lateralis muscle of the leg, the ventrogluteal muscles of the hips, the dorsogluteal muscles of the buttocks, the diaphragm and the intercostal muscles of the rib cage. 
     In certain embodiments, the therapeutic agents of the disclosure can be delivered by transdermal methods (e.g., via incorporation of the modified antisense oligomers into, e.g., emulsions, with such modified antisense oligomers optionally packaged into liposomes). Such transdermal and emulsion/liposome-mediated methods of delivery are described for delivery of modified antisense oligomers in the art, e.g., in U.S. Pat. No. 6,965,025, which are hereby incorporated by reference in their entirety. 
     The therapeutic agents described herein may also be delivered via an implantable device. Design of such a device is an art-recognized process, with, e.g., synthetic implant design described in, e.g., U.S. Pat. No. 6,969,400, which are hereby incorporated by reference in their entirety. 
     Therapeutic agents can be introduced into cells using art-recognized techniques (e.g., transfection, electroporation, fusion, liposomes, colloidal polymeric particles and viral and non-viral vectors as well as other means known in the art). The method of delivery selected will depend, for example, on the oligomer chemistry, the cells to be treated and the location of the cells and will be apparent to the skilled artisan. For instance, localization can be achieved by liposomes with specific markers on the surface to direct the liposome, direct injection into tissue containing target cells, specific receptor-mediated uptake, or the like. 
     As known in the art, therapeutic agents may be delivered using, e.g., methods involving liposome-mediated uptake, lipid conjugates, polylysine-mediated uptake, nanoparticle-mediated uptake, and receptor-mediated endocytosis, as well as additional non-endocytic modes of delivery, such as microinjection, permeabilization (e.g., streptolysin-O permeabilization, anionic peptide permeabilization), electroporation, and various non-invasive non-endocytic methods of delivery that are known in the art (refer to Dokka and Rojanasakul, Advanced Drug Delivery Reviews 44, 35-49 (2000), which is hereby incorporated by reference in its entirety). 
     The therapeutic agents may be administered in any convenient vehicle or carrier which is physiologically and/or pharmaceutically acceptable. Such a composition may include any of a variety of standard pharmaceutically acceptable carriers employed by those of ordinary skill in the art. Examples include, but are not limited to, saline, phosphate buffered saline (PBS), water, aqueous ethanol, emulsions, such as oil/water emulsions or triglyceride emulsions, tablets and capsules. The choice of suitable physiologically acceptable carrier will vary dependent upon the chosen mode of administration. “Pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions. 
     The modified antisense oligomers of the present disclosure may generally be utilized as the free acid or free base. Alternatively, the compounds of this disclosure may be used in the form of acid or base addition salts. Acid addition salts of the free amino compounds of the present disclosure may be prepared by methods well known in the art, and may be formed from organic and inorganic acids. Suitable organic acids include maleic, fumaric, benzoic, ascorbic, succinic, methanesulfonic, acetic, trifluoroacetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, glycolic, glutamic, and benzenesulfonic acids. 
     Suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, phosphoric, and nitric acids. Base addition salts included those salts that form with the carboxylate anion and include salts formed with organic and inorganic cations such as those chosen from the alkali and alkaline earth metals (for example, lithium, sodium, potassium, magnesium, barium and calcium), as well as the ammonium ion and substituted derivatives thereof (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term “pharmaceutically acceptable salt” is intended to encompass any and all acceptable salt forms. 
     In addition, prodrugs are also included within the context of this disclosure. Prodrugs are any covalently bonded carriers that release a compound in vivo when such prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups in a way such that the modification is cleaved, either by routine manipulation or in vivo, yielding the parent compound. Prodrugs include, for example, compounds of this disclosure where hydroxy, amine or sulfhydryl groups are bonded to any group that, when administered to a patient, cleaves to form the hydroxy, amine or sulfhydryl groups. Thus, representative examples of prodrugs include (but are not limited to) acetate, formate and benzoate derivatives of alcohol and amine functional groups of the modified antisense oligomers of the disclosure. Further, in the case of a carboxylic acid (—COOH), esters may be employed, such as methyl esters, ethyl esters, and the like. 
     In some instances, liposomes may be employed to facilitate uptake of the modified antisense oligomer into cells (see, e.g., Williams, S. A., Leukemia 10(12):1980-1989, 1996; Lappalainen et al., Antiviral Res. 23:119, 1994; Uhlmann et al., modified antisense oligomers: a new therapeutic principle, Chemical Reviews, Volume 90, No. 4, 25 pages 544-584, 1990; Gregoriadis, G., Chapter 14, Liposomes, Drug Carriers in Biology and Medicine, pp. 287-341, Academic Press, 1979). Hydrogels may also be used as vehicles for modified antisense oligomer administration, for example, as described in PCT Publication No. WO 1993/01286. Alternatively, the oligomers may be administered in microspheres or microparticles. (See, e.g., Wu, G. Y. and Wu, C. H., J. Biol. Chem. 262:4429-4432, 30 1987). Alternatively, the use of gas-filled microbubbles complexed with the modified antisense oligomers can enhance delivery to target tissues, as described in U.S. Pat. No. 6,245,747. Sustained release compositions may also be used. These may include semipermeable polymeric matrices in the form of shaped articles such as films or microcapsules. Each such reference is hereby incorporated by reference in their entirety. 
     In some embodiments, the therapeutic agent is administered in an amount and manner effective to result in a peak blood concentration of at least 200-400 nM of therapeutic agent. Typically, one or more doses of therapeutic agent are administered, generally at regular intervals, for a period of about one to two weeks. Preferred doses for oral administration are from about 1-1000 mg oligomer per 70 kg. In some cases, doses of greater than 1000 mg oligomer/patient may be necessary. For i.v. administration, preferred doses are from about 0.5 mg to 1000 mg oligomer per 70 kg. The therapeutic agent may be administered at regular intervals for a short time period, e.g., daily for two weeks or less. However, in some cases the therapeutic agent is administered intermittently over a longer period of time. Administration may be followed by, or concurrent with, administration of an antibiotic or other therapeutic treatment. The treatment regimen may be adjusted (dose, frequency, route, etc.) as indicated, based on the results of immunoassays, other biochemical tests and physiological examination of the subject under treatment. 
     An effective in vivo treatment regimen using the therapeutic agents of the disclosure may vary according to the duration, dose, frequency and route of administration, as well as the condition of the subject under treatment (i.e., prophylactic administration versus administration in response to localized or systemic infection). Accordingly, such in vivo therapy will often require monitoring by tests appropriate to the particular type of disorder under treatment, and corresponding adjustments in the dose or treatment regimen, in order to achieve an optimal therapeutic outcome. 
     Treatment may be monitored, e.g., by general indicators of disease known in the art. The efficacy of an in vivo administered therapeutic agent may be determined from biological samples (tissue, blood, urine etc.) taken from a subject prior to, during and subsequent to administration of the therapeutic agent. Assays of such samples, wherein the therapeutic agent is a modified antisense oligomer, include (1) monitoring the presence or absence of heteroduplex formation with target and non-target sequences, using procedures known to those skilled in the art, e.g., an electrophoretic gel mobility assay; (2) monitoring the amount of an mRNA which does not comprise myostatin exon 2 in relation to a reference exon 2-containing myostatin mRNA; or (3) monitoring the amount of an mRNA which does not comprise dystrophin mRNA containing one or more exons having one or more genetic mutations in relation to a reference dystrophin mRNA containing one or more genetic mutations, as determined by standard techniques such as RT-PCR, northern blotting, ELISA or western blotting. In some embodiments, treatment is monitored by symptomatic assessments. Those assessments include, but not limited to, self-evalulation, physician&#39;s examinations, motor function tests (e.g., grip strength tests) including measurements of muscle size, muscle mass, strength, reflex, involuntary muscle movements, electrophysiology test, number of muscle fibers and fibers with centralized nuclei, and cardiovascular function tests including electrocardiogram (EKG or EGG). 
     In some embodiments, the methods described herein also include administration in combination with another therapeutic. The additional therapeutic may be administered prior, concurrently or non-concurrently, for example subsequently, to the administration of the therapeutic(s) of the present invention. For example, the therapeutic may be administered in combination with a steroid and/or an antibiotic. In another example, the patient has been treated with a corticosteroid (e.g., a stable dose of a corticosteroid for four to six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 or more weeks) prior to administration of eteplirsen. The steroid may be a glucocorticoid or prednisone. Glucocorticoids such as cortisol control carbohydrate, fat and protein metabolism, and are anti-inflammatory by preventing phospholipid release, decreasing eosinophil action and a number of other mechanisms. Mineralocorticoids such as aldosterone control electrolyte and water levels, mainly by promoting sodium retention in the kidney. Corticosteroids are a class of chemicals that includes steroid hormones naturally produced in the adrenal cortex of vertebrates and analogues of these hormones that are synthesized in laboratories. Corticosteroids are involved in a wide range of physiological processes, including stress response, immune response, and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior. Corticosteroids include, but are not limited to, Betamethasone, Budesonide, Cortisone, Dexamethasone, Hydrocortisone, Methylprednisolone, Prednisolone, and Prednisone. One particular steroid of interest that may h administered prior, concurrently or subsequently to the administration of the composition of the present invention is deflazacort and formulations thereof (e.g., MP-104, Marathon Pharmaceuticals LLC). 
     In some embodiments, the dosage of a therapeutic (e.g., a therapeutic oligonucleotide, such as eteplirsen) is about 30 mg/kg over a period of time sufficient to treat DMD. In some embodiments, the therapeutic is administered to the patient at a dose of between about 25 mg/kg and about 50 mg/kg (e.g., about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 mg/kg), once per week. In some embodiments, the therapeutic is administered to the patient at a dose of between about 25 mg/kg, and about 50 mg/kg (e.g., about 30 mg/kg to about 50 ng/kg, about 25 mg/kg to about 40 mg/kg, about 28 mg/kg to about 32 mg/kg, or about 30 mg/kg to about 40 mg/kg), e.g., once per week. 
     In some embodiments, the therapeutic is administered intravenously once a week. In certain embodiments, the time of infusion is from about 15 minutes to about 4 hours. In some embodiments, the time of infusion is from about 30 minutes to about 3 hours. In some embodiments, the time of infusion is from about 30 minutes to about 2 hours. In some embodiments, the time of infusion is from about 1 hour to about 2 hours. In some embodiments the time of infusion is from about 30 minutes to about 1 hour. In some embodiments, the time of infusion is about 60 minutes. In some embodiments, the time of infusion is 35 to 60 minutes. 
     VI. DOSING 
     The formulation of therapeutic compositions and their subsequent administration (dosing) 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 oligomers, and can generally be estimated based on EC50s found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 μg 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, where the oligomer is administered in maintenance doses, ranging from 1-1000 mg oligomer per 70 kg of body weight for oral administration, or 0.5 mg to 1000 mg oligomer per 70 kg of body weight for i.v. administration, once or more daily, to once every 20 years. 
     While the present disclosure has been described with specificity in accordance with certain of its embodiments, the following examples serve only to illustrate the disclosure and are not intended to limit the same. Each of the references, patents, patent applications, GenBank accession numbers, and the like recited in the present application are hereby incorporated by reference in its entirety. 
     VI. EXAMPLES 
     The following Examples may be used for illustrative purposes and should not be deemed to narrow the scope of the invention. 
     Modified antisense oligomers (illustrated in  FIGS. 1A to 1G ) of the disclosure were designed to bind to a target region within a dystrophin or myostatin pre-mRNA transcript and prepared using the following protocol: 
     Procedure a for the Preparation of Active Subunits: 
     
       
         
         
             
             
         
       
     
     To a stirred solution of 6 (1 eq) in dichloromethane was added POCl3 (1.1 eq), followed by diisopropylethylamine (3 eq) at 0° C., cooled by an ice-bath. After 15 minutes, the ice-bath was removed and the solution was allowed to warm to room temperature for one hour. Upon reaction completion, the reaction solution was diluted with dichloromethane, washed with 10% aqueous citric acid three times. After drying over MgSO4, the organic layer was passed through a plug of silica gel and concentrated in vacuo. The resulting phosphoroamidodichloride (4) was used directly for the next step without further purification. 
     To a solution of the phosphoroamidodichloride (4) (1 eq), 2,6-lutidine (1 eq) in dichloromethane was added Mo(Tr)T (7) (0.5 eq)/dichloromethane solution, followed by N-methylimidazole (0.2 eq). The reaction stirred at room temperature overnight. Upon reaction completion, the reaction solution was diluted with dichloromethane, and washed with 10% aqueous citric acid three times. After drying over MgSO 4 , the organic layer was filtered, then concentrated. The product (8) was purified by silica gel chromatography (eluting with a gradient of ethyl acetate/hexanes), and then stored at −20° C. The structure was confirmed by LCMS analysis. 
     Procedure B for the Preparation of Activated Subunits: 
     
       
         
         
             
             
         
       
     
     To a solution of POCl 3  (l.leq) in dichloromethane was added 2,6-lutidine (2 eq), followed by dropwise addition of Mo(Tr)T (7) (leq)/dichloromethane solution at 0° C. After 1 hour, the reaction solution was diluted with dichloromethane, and quickly washed three times with 10% aqueous citric acid. The desired phosphodichloridate (9) was obtained after drying over MgSO 4  and evaporation of solvent. 
     To a solution of the phosphodichloridate (leq) in dichloromethane was added amine (leq)/dichloromethane dropwise to the solution at 0° C. After 15 minutes, the reaction mixture was allowed to warm to room temperature for about an hour. Upon reaction completion, the product (8) as a white solid was collected by precipitation with the addition of hexanes, followed by filtration. The product was stored at −20° C. after drying under vacuum. The structure was confirmed by LCMS analysis. 
     Example 1: ((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl Phosphorodichloridate 
     
       
         
         
             
             
         
       
     
     To a cooled (ice/water bath) DCM solution (20 mL) of phosphorus oxychloride (2.12 mL, 22.7 mmol) was added dropwise 2,6-lutidine (4.82 mL, 41.4 mmol) then a DCM solution (20 mL) Mo(Tr)T (2) (10.0 g, 20.7 mmol) was added dropwise over 15 min (int. temp. 0-10° C.) then bath was removed a stirring continued at ambient temperature for 20 min. The reaction was washed with citric acid solution (40 mL×3, 10% w/v aq), dried (MgSO4), filtered and concentrated to a white foam (9.79 g) then used directly for the following procedure. 
     Example 2: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-(dimethylamino)piperidin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     To a cooled (ice/water bath) DCM solution (5 mL) of the dichlorophosphate from example 1 (5.00 g, 5.00 mmol) was added a DCM solution (5 mL) of the piperidine (0.61 g, 4.76 mmol) dropwise then the bath was removed and stirring continued at ambient temperature for 30 min. The reaction was loaded directly onto a column. Chromatography with [SiO2 column (40 g), DCM/EtOH eluant (gradient 1:0 to 1:1)] afforded the title compound (2.5 g) as a white foam. ESI/MS calcd. for 1 (4 nitrophenyl)piperazine derivative C46H55N8O7P 862.4, found m/z=863.6 (M+1). 
     Example 3: 1-(1-(chloro((6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methoxy)phosphoryl)piperidin-4-yl)-1-methylpyrrolidin-1-ium Chloride 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized in a manner analogous to that described in Example 2 to afford the title compound (0.6 g) as a white solid. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C 49 H 60 N 8 O 7 P 903.4, found m/z=903.7 (M+). 
     Example 4: ((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-methylpiperazin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     To a cooled (ice/water bath) DCM solution (10 mL) of phosphorus oxychloride (1.02 mL, 11.0 mmol) was added dropwise 2,6-lutidine (3.49 mL, 29.9 mmol) then a DCM solution (10 mL) of methyl piperazine (1.00 g, 10.0 mmol) was added dropwise and stirring continued for 1 h. A DCM solution (10 mL) of Mo(Tr)T (2) (4.82, 10.0 mmol) and NMI (79 μL, 1.0 mmol) was added and stirred 4 h then loaded directly onto a column. 
     Chromatography with [SiO2 column (80 g), DCM/Acetone with 2% TEA eluant (gradient 1:0 to 0:1)] afforded the title compound (0.8 g) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C43H48N708P 834.4, found m/z=835.5 (M+1). 
     Example 5: ((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-ethylpiperazin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized in a manner analogous to that described in Example 4 to afford the title compound (11.5 g) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C45H53N8O7P 848.4, found m/z=849.7 (M+1). 
     Example 6: ((2S,6R)-6-(6-benzamido-9H-purin-9-yl)-4-tritylmorpholin-2-yl)methyl (4-ethylpiperazin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized in a manner analogous to that described in Example 4 to afford the title compound (4.5 g) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C52H56N11O6P 961.4, found m/z=962.8 (M+1). 
     Example 7: ((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-isopropylpiperazin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized in a manner analogous to that described in Example 4 to afford the title compound (3.5 g) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C 46 H 55 N 8 O 7 P 862.4, found m/z=863.7 (M+1). 
     Example 8: ((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl methyl(2-(2,2,2-trifluoroacetamido)ethyl)phosphoramidochloridate 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized in a manner analogous to that described in Example 4 to afford the title compound (1.0 g) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C 44 H 48 F 3 N 8 O 8 P 904.3, found m/z=903.7 (M−1). 
     Example 9: ((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl methyl(2-(2,2,2-trifluoro-N-methylacetamido)ethyl)phosphoramidochloridate 
     
       
         
         
             
             
         
       
     
     The title compound was synthesized in a manner analogous to that described in Example 4 to afford the title compound (1.8 g) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C 45 H 50 F 3 N 8 O 8 P 918.3, found m/z=1836.6 (2M+). 
     Example 10: ((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-(2,2,2-trifluoroacetamido)piperidin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     To a cooled solution (ice/water bath) of phosphorus oxychloride (17.7 mL, 190 mmol) in DCM (190 mL) was added dropwise 2,6-lutidine (101 mL, 864 mmol) then Mo(Tr)T (2) (83.5 g, 173 mmol) portionwise over 15 min (int. temp. 0-10° C.) and stirred. After 30 min, the 4-aminopiperidine monotrifluoroacetamide (48.9 g, ˜190 mmol) was added dropwise over 15 min (int. temp. 0-8° C.) and stirred. After 1 h, DIPEA (50 mL) was added dropwise (int. temp. 0-10° C.) and stirred 1 h. The reaction was washed with citric acid solution (500 mL×3, 10% w/v aq), dried (MgSO4), filtered and concentrated to a viscous oil which was loaded directly onto a column. Chromatography with [SiO2 column (330 g), hexanes/EtOAc eluant (gradient 1:0 to 0:1)] afforded the title compound (91.3 g, 70% yield) as a white foam. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C43H48N708P 930.9, found m/z=954.4 (M+Na). 
     Examples 11 through 14 were prepared via procedure A described above. 
     Example 11: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-(1-(2,2,2-trifluoroacetyl)piperidin-4-yl)piperazin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     Example 12: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-morpholinopiperidine-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     Example 13: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl bis(3-(2,2,2-trifluoroacetamido)propyl)phosphoramidochloridate 
     
       
         
         
             
             
         
       
     
     Example 14: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl) methyl [1,4′-bipiperidin]-1′-ylphosphonochloridate 
     
       
         
         
             
             
         
       
     
     Examples 15 through 20 below were prepared via procedure B described above. 
     Example 15: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-(pyrimidin-2-yl)piperazin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     Example 16: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-(2-(dimethylamino)ethyl)piperazin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     Example 17: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-phenylpiperazin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     Example 18: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-(2,2,2-trifluoro-N-methylacetamido)piperidin-1-yl)phosphorochloridate 
     
       
         
         
             
             
         
       
     
     Example 19: (6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl methyl(3-(2,2,2-trifluoro-N-methylacetamido)propyl)phosphoramidochloridate 
     
       
         
         
             
             
         
       
     
     Example 20: ((2S,6R)-6-(6-benzamido-9H-purin-9-yl)-4-tritylmorpholin-2-yl)methyl (4-(2,2,2-trifluoroacetamido)piperidin-1-yl)phosphonochloridate 
     
       
         
         
             
             
         
       
     
     Example 21: (4-(pyrrolidin-1-yl)piperidin-1-yl)phosphonic Dichloride Hydrochloride 
     To a cooled (ice/water bath) solution of phosphorus oxychloride (5.70 mL, 55.6 mmol) in DCM (30 mL) was added 2,6-lutidine (19.4 mL, 167 mmol) and a DCM solution (30 mL) of 4-(1-pyrrolidinyl)-piperidine (8.58 g, 55.6 mmol) and stirred for 1 hour. The suspension was filtered and solid washed with excess diethyl ether to afford the title pyrrolidine (17.7 g, 91% yield) as a white solid. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C 19 H 30 N 5 O 4 P 423.2, found m/z=422.2 (M−1). 
     
       
         
         
             
             
         
       
     
     Example 22: ((2S,6R)-6-(5-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-tritylmorpholin-2-yl)methyl (4-(pyrrolidin-1-yl)piperidin-1-yl)phosphonochloridate Hydrochloride 
     
       
         
         
             
             
         
       
     
     To a stirred, cooled (ice/water bath) solution of the dichlorophosphoramidate from Example 21 (17.7 g, 50.6 mmol) in DCM (100 mL) was added a DCM solution (100 mL) of Mo(Tr)T (2) (24.5 g, 50.6 mmol), 2,6-Lutidine (17.7 mL, 152 mmol), and 1-methylimidazole (0.401 mL, 5.06 mmol) dropwise over 10 minutes. The bath was allowed to warm to ambient temperature as suspension was stirred. After 6 hours, the suspension was poured onto diethyl ether (1 L), stirred 15 minutes, filtered and solid washed with additional ether to afford a white solid (45.4 g). The crude product was purified by chromatography [SiO 2  column (120 gram), DCM/MeOH eluant (gradient 1:0 to 6:4)], and the combined fractions were poured onto diethyl ether (2.5 L), stirred 15 min, filtered, and the resulting solid washed with additional ether to afford the title compound (23.1 g, 60% yield) as a white solid. ESI/MS calcd. for 1-(4-nitrophenyl)piperazine derivative C 48 H 57 N 8 O 7 P 888.4, found m/z=887.6 (M−1). 
     Example 23 
     Design and Manufacture of Modified Antisense Oligomers and Exemplary Modified Antisense Oligomers 
     Preparation of trityl piperazine phenyl carbamate 35 ( FIG. 2A ): To a cooled suspension of compound 11 in dichloromethane (6 mL/g 11) was added a solution of potassium carbonate (3.2 eq) in water (4 mL/g potassium carbonate). To this two-phase mixture was slowly added a solution of phenyl chloroformate (1.03 eq) in dichloromethane (2 g/g phenyl chloroformate). The reaction mixture was warmed to 20° C. Upon reaction completion (1-2 hr), the layers were separated. The organic layer was washed with water, and dried over anhydrous potassium carbonate. The product 35 was isolated by crystallization from acetonitrile. 
     Preparation of carbamate alcohol 36: Sodium hydride (1.2 eq) was suspended in 1-methyl-2-pyrrolidinone (32 mL/g sodium hydride). To this suspension were added triethylene glycol (10.0 eq) and compound 35 (1.0 eq). The resulting slurry was heated to 95° C. Upon reaction completion (1-2 hr), the mixture was cooled to 20° C. To this mixture was added 30% dichloromethane/methyl tert-butyl ether (v:v) and water. The product-containing organic layer was washed successively with aqueous NaOH, aqueous succinic acid, and saturated aqueous sodium chloride. The product 36 was isolated by crystallization from dichloromethane/methyl tert-butyl ether/heptane. 
     Preparation of Tail acid 37: To a solution of compound 36 in tetrahydrofuran (7 mL/g 36) was added succinic anhydride (2.0 eq) and DMAP (0.5 eq). The mixture was heated to 50° C. Upon reaction completion (5 hr), the mixture was cooled to 20° C. and adjusted to pH 8.5 with aqueous NaHCO 3 . Methyl tert-butyl ether was added, and the product was extracted into the aqueous layer. Dichloromethane was added, and the mixture was adjusted to pH 3 with aqueous citric acid. The product-containing organic layer was washed with a mixture of pH=3 citrate buffer and saturated aqueous sodium chloride. This dichloromethane solution of 37 was used without isolation in the preparation of compound 38. 
     Preparation of 38: To the solution of compound 37 was added N-hydroxy-5-norbornene-2,3-dicarboxylic acid imide (HONB) (1.02 eq), 4-dimethylaminopyridine (DMAP) (0.34 eq), and then 1-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (1.1 eq). The mixture was heated to 55° C. Upon reaction completion (4-5 hr), the mixture was cooled to 20° C. and washed successively with 1:1 0.2 M citric acid/brine and brine. The dichloromethane solution underwent solvent exchange to acetone and then to N,N-dimethylformamide, and the product was isolated by precipitation from acetone/N,N-dimethylformamide into saturated aqueous sodium chloride. The crude product was reslurried several times in water to remove residual N,N-dimethylformamide and salts. 
     Introduction of the activated “Tail” onto the anchor-loaded resin was performed in dimethyl imidazolidinone (DMI) by the procedure used for incorporation of the subunits during solid phase synthesis. 
     Preparation of the Solid Support for Synthesis of morpholino-based oligomers: This procedure was performed in a silanized, jacketed peptide vessel (ChemGlass, NJ, USA) with a coarse porosity (40-60 μm) glass frit, overhead stirrer, and 3-way Teflon stopcock to allow N2 to bubble up through the frit or a vacuum extraction. 
     The resin treatment/wash steps in the following procedure consist of two basic operations: resin fluidization or stirrer bed reactor and solvent/solution extraction. For resin fluidization, the stopcock was positioned to allow N2 flow up through the frit and the specified resin treatment/wash was added to the reactor and allowed to permeate and completely wet the resin. Mixing was then started and the resin slurry mixed for the specified time. For solvent/solution extraction, mixing and N2 flow were stopped and the vacuum pump was started and then the stopcock was positioned to allow evacuation of resin treatment/wash to waste. All resin treatment/wash volumes were 15 mL/g of resin unless noted otherwise. 
     To aminomethylpolystyrene resin (100-200 mesh; ˜1.0 mmol/g load based on nitrogen substitution; 75 g, 1 eq, Polymer Labs, UK, part #1464-X799) in a silanized, jacketed peptide vessel was added 1-methyl-2-pyrrolidinone (NMP; 20 ml/g resin) and the resin was allowed to swell with mixing for 1-2 hr. Following evacuation of the swell solvent, the resin was washed with dichloromethane (2×1-2 min), 5% diisopropylethylamine in 25% isopropanol/dichloromethane (2×3-4 min) and dichloromethane (2×1-2 min). After evacuation of the final wash, the resin was treated with a solution of disulfide anchor 34 in 1-methyl-2-pyrrolidinone (0.17 M; 15 mL/g resin, ˜2.5 eq) and the resin/reagent mixture was heated at 45° C. for 60 hr. On reaction completion, heating was discontinued and the anchor solution was evacuated and the resin washed with 1-methyl-2-pyrrolidinone (4×3-4 min) and dichloromethane (6×1-2 min). The resin was treated with a solution of 10% (v/v) diethyl dicarbonate in dichloromethane (16 mL/g; 2×5-6 min) and then washed with dichloromethane (6×1-2 min). The resin 39 ( FIG. 2B ) was dried under a N 2  stream for 1-3 hr and then under vacuum to constant weight (±2%). Yield: 110-150% of the original resin weight. 
     Determination of the Loading of Aminomethylpolystyrene-disulfide resin: The loading of the resin (number of potentially available reactive sites) is determined by a spectrometric assay for the number of triphenylmethyl (trityl) groups per gram of resin. 
     A known weight of dried resin (25±3 mg) is transferred to a silanized 25 ml volumetric flask and ˜5 mL of 2% (v/v) trifluoroacetic acid in dichloromethane is added. The contents are mixed by gentle swirling and then allowed to stand for 30 min. The volume is brought up to 25 mL with additional 2% (v/v) trifluoroacetic acid in dichloromethane and the contents thoroughly mixed. Using a positive displacement pipette, an aliquot of the trityl-containing solution (500 μL) is transferred to a 10 mL volumetric flask and the volume brought up to 10 mL with methanesulfonic acid. 
     The trityl cation content in the final solution is measured by UV absorbance at 431.7 nm and the resin loading calculated in trityl groups per gram resin μmol/g) using the appropriate volumes, dilutions, extinction coefficient (ε: 41 μmol-1 cm-1) and resin weight. The assay is performed in triplicate and an average loading calculated. 
     The resin loading procedure in this example will provide resin with a loading of approximately 500 μmol/g. A loading of 300-400 in μmol/g was obtained if the disulfide anchor incorporation step is performed for 24 hr at room temperature. 
     Tail loading: Using the same setup and volumes as for the preparation of aminomethylpolystyrene-disulfide resin, the Tail can be introduced into solid support. The anchor loaded resin was first deprotected under acidic condition and the resulting material neutralized before coupling. For the coupling step, a solution of 38 (0.2 M) in DMI containing 4-ethylmorpholine (NEM, 0.4 M) was used instead of the disulfide anchor solution. After 2 hr at 45° C., the resin 39 was washed twice with 5% diisopropylethylamine in 25% isopropanol/dichloromethane and once with DCM. To the resin was added a solution of benzoic anhydride (0.4 M) and NEM (0.4 M). After 25 min, the reactor jacket was cooled to room temperature, and the resin washed twice with 5% diisopropylethylamine in 25% isopropanol/dichloromethane and eight times with DCM. The resin 40 was filtered and dried under high vacuum. The loading for resin 40 is defined to be the loading of the original aminomethylpolystyrene-disulfide resin 39 used in the Tail loading. 
     Solid Phase Synthesis: morpholino-based oligomers were prepared on a Gilson AMS-422 Automated Peptide Synthesizer in 2 mL Gilson polypropylene reaction columns (Part #3980270). An aluminum block with channels for water flow was placed around the columns as they sat on the synthesizer. The AMS-422 will alternatively add reagent/wash solutions, hold for a specified time, and evacuate the columns using vacuum. 
     For oligomers in the range up to about 25 subunits in length, aminomethylpolystyrene-disulfide resin with loading near 500 μmol/g of resin is preferred. For larger oligomers, aminomethylpolystyrene-disulfide resin with loading of 300-400 μmol/g of resin is preferred. If a molecule with 5′-Tail is desired, resin that has been loaded with Tail is chosen with the same loading guidelines. 
     The following reagent solutions were prepared: 
     Detritylation Solution: 10% Cyanoacetic Acid (w/v) in 4:1 dichloromethane/acetonitrile; Neutralization Solution: 5% Diisopropylethylamine in 3:1 dichloromethane/isopropanol; Coupling Solution: 0.18 M (or 0.24 M for oligomers having grown longer than 20 subunits) activated morpholino subunit of the desired base and linkage type and 0.4 M N ethylmorpholine, in 1,3-dimethylimidazolidinone. Dichloromethane (DCM) was used as a transitional wash separating the different reagent solution washes. 
     On the synthesizer, with the block set to 42° C., to each column containing 30 mg of aminomethylpolystyrene-disulfide resin (or Tail resin) was added 2 mL of 1-methyl-2-pyrrolidinone and allowed to sit at room temperature for 30 min. After washing with 2 times 2 mL of dichloromethane, the following synthesis cycle was employed: 
     
       
         
           
               
             
               
                 TABLE 6 
               
             
            
               
                   
               
               
                 Synthesis Cycle for Modified Antisense Oligomers 
               
            
           
           
               
               
               
               
               
            
               
                   
                 Step 
                 Volume 
                 Delivery 
                 Hold time 
               
               
                   
                   
               
            
           
           
               
               
               
               
               
               
            
               
                   
                 Detritylation 
                 1.5 
                 mL 
                 Manifold 
                 15 sec. 
               
               
                   
                 Detritylation 
                 1.5 
                 mL 
                 Manifold 
                 15 sec. 
               
               
                   
                 Detritylation 
                 1.5 
                 mL 
                 Manifold 
                 15 sec. 
               
               
                   
                 Detritylation 
                 1.5 
                 mL 
                 Manifold 
                 15 sec. 
               
               
                   
                 Detritylation 
                 1.5 
                 mL 
                 Manifold 
                 15 sec. 
               
               
                   
                 Detritylation 
                 1.5 
                 mL 
                 Manifold 
                 15 sec. 
               
               
                   
                 Detritylation 
                 1.5 
                 mL 
                 Manifold 
                 15 sec. 
               
               
                   
                 DCM 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 Neutralization 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 Neutralization 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 Neutralization 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 Neutralization 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 Neutralization 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 Neutralization 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 DCM 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 Coupling 
                 350-500 
                 uL 
                 Syringe 
                 40 min. 
               
               
                   
                 DCM 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 Neutralization 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 Neutralization 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 DCM 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 DCM 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                 DCM 
                 1.5 
                 mL 
                 Manifold 
                 30 sec. 
               
               
                   
                   
               
            
           
         
       
     
     The sequences of the individual oligomers were programmed into the synthesizer so that each column receives the proper coupling solution (A,C,G,T,I) in the proper sequence. When the oligomer in a column had completed incorporation of its final subunit, the column was removed from the block and a final cycle performed manually with a coupling solution comprised of 4-methoxytriphenylmethyl chloride (0.32 M in DMO containing 0.89 M 4-ethylmorpholine. 
     Cleavage from the resin and removal of bases and protecting groups: After methoxytritylation, the resin was washed 8 times with 2 mL 1-methyl-2-pyrrolidinone. One mL of a cleavage solution comprising 0.1 M 1,4-dithiothreitol (DTT) and 0.73 M triethylamine in 1-methyl-2-pyrrolidinone was added, the column capped, and allowed to sit at room temperature for 30 min. After that time, the solution was drained into a 12 mL Wheaton vial. The greatly shrunken resin was washed twice with 300 μl of cleavage solution. To the solution was added 4.0 mL conc. Aqueous ammonia (stored at −20° C.), the vial capped tightly (with Teflon lined screw cap), and the mixture swirled to mix the solution. The vial was placed in a 45° C. oven for 16-24 hr to effect cleavage of base and protecting groups. 
     Crude product purification: The vialed ammonolysis solution was removed from the oven and allowed to cool to room temperature. The solution was diluted with 20 mL of 0.28% aqueous ammonia and passed through a 2.5×10 cm column containing Macroprep HQ resin (BioRad). A salt gradient (A: 0.28% ammonia with B: 1 M sodium chloride in 0.28% ammonia; 0-100% B in 60 min) was used to elute the methoxytrityl containing peak. The combined fractions were pooled and further processed depending on the desired product. 
     Demethoxytritylation of morpholino-based oligomers: The pooled fractions from the Macroprep purification were treated with 1 M H3PO4 to lower the pH to 2.5. After initial mixing, the samples sat at room temperature for 4 min, at which time they are neutralized to pH 10-11 with 2.8% ammonia/water. The products were purified by solid phase extraction (SPE). 
     SPE column packing and conditioning: Amberchrome CG-300M (Rohm and Haas; Philadelphia, Pa.) (3 mL) is packed into 20 mL fritted columns (BioRad Econo-Pac Chromatography Columns (732-1011)) and the resin rinsed with 3 mL of the following: 0.28% NH 4 OH/80% acetonitrile; 0.5M NaOH/20% ethanol; water; 50 mM H3PO4/80% acetonitrile; water; 0.5 NaOH/20% ethanol; water; 0.28% NH 4 OH. 
     SPE purification: The solution from the demethoxytritylation was loaded onto the column and the resin rinsed three times with 3-6 mL 0.28% aqueous ammonia. A Wheaton vial (12 mL) was placed under the column and the product eluted by two washes with 2 mL of 45% acetonitrile in 0.28% aqueous ammonia. 
     Product isolation: The solutions were frozen in dry ice and the vials placed in a freeze dryer to produce a fluffy white powder. The samples were dissolved in water, filtered through a 0.22 micron filter (Pall Life Sciences, Acrodisc 25 mm syringe filter, with a 0.2 micron HT Tuffryn membrane) using a syringe and the Optical Density (OD) was measured on a UV spectrophotometer to determine the OD units of oligomer present, as well as dispense sample for analysis. The solutions were then placed back in Wheaton vials for lyophilization. 
     Analysis of morpholino-based oligomers by MALDI: MALDI-TOF mass spectrometry was used to determine the composition of fractions in purifications as well as provide evidence for identity (molecular weight) of the oligomers. Samples were run following dilution with solution of 3,5-dimethoxy-4-hydroxycinnamic acid (sinapinic acid), 3,4,5-trihydoxyacetophenone (THAP) or alpha-cyano-4-hydoxycinnamic acid (HCCA) as matrices. 
     Example 24 In Vivo Screening of PMO Myostatin Sequences 
     PMO sequences designed to skip myostatin exon 2 were screened. The efficacy of the PMO sequences was tested in vitro in both human Rhabdomyosarcoma (RD) and murine myoblast (normal—C2C12 and dystrophic—H2Kbmdx) cells. Four human-specific PMOs targeting the 5′ end of myostatin exon 2 were subsequently screened in RD cells. 
     PMOs were transfected by Nucleofection (Neon transfection system, Life technologies, Carlsbad, Calif.) following the manufacturer&#39;s standard protocol. Skipping efficiency of PMOs was evaluated by semi-quantitative RT-PCRs following densitometric analysis of gel electrophoresis results of RT-PCR products as a percentage of the density of skipped products against the total density of skipped and unskipped products. The sequences are listed in Table 7. 
     Sequences PMO 39, SEQ ID NO: 48, PMO 42, SEQ ID NO: 16, PMO 43, SEQ ID NO: 49, PMO 44, SEQ ID NO: 17, PMO 45, SEQ ID NO: 18, and PMO 124 were designed to bind both murine and human myostatin exon 2. PMOs were tested in triplicate at 4 doses (0.25, 0.5, 1, 2 μM). Myostatin exon 2 skipping efficiency was evaluated by RT-PCR ( FIG. 3A ) and densitometric analysis of the RT-PCR products as described above as a percentage of the intensity of skipped products against the total intensity of skipped and unskipped products. Statistical analysis was performed by one-way ANOVA for individual dose comparing the efficiency of the PMOs with that of PMO 28, (synthesized by GeneTools) which was demonstrated as an effective PMO to skip myostatin exon 2 ( FIG. 3B ). 
     Four (4) human specific PMOs (PMO 40, PMO 46, SEQ ID NO: 21, PMO 47, SEQ ID NO: 20, PMO 48, SEQ ID NO: 19) were analysed that were all designed to bind the 5′ end of human myostatin exon 2. PMOs were tested in triplicate at 1 μM dose and compared with the PMOs targeting the 3′ end at the same concentration. As these PMOs were expected to induce exon 2 skipping, their efficacy was assessed by the established RT-PCR protocol following a densitometric analysis as mentioned above. Results of the RT-PCT products are shown in  FIG. 4A  and the densitometric analysis is shown in  FIG. 4B . 
     Among the PMOs targeting the 3′ end of myostatin exon 2, PMOs 44, SEQ ID NO: 17 and 45, SEQ ID NO: 18 (and, at higher concentration, PMO 39, SEQ ID NO: 48) induced more consistent skipping than others, particularly at lower concentrations ( FIG. 4B ). The skipping efficacy was even higher when PMOs targeting 5′ end of myostatin exon 2 were used, with PMO 46, SEQ ID NO: 21 inducing nearly 100% skipping and PMOs 40 and 48, SEQ ID NO: 19 inducing about 80% skipping ( FIG. 4B ). 
     Screening of PMOs for Skipping Exon 2 of Mouse Myostatin: A Dose-Response Study for PMOs 39, 42, 43, 44, 45, 124 in C2C12 and H2Kbmdxcells 
     The first example of specific and reproducible exon skipping in the mdx mouse model was reported by Wilton et al. (Wilton, Lloyd et al. 1999; the contents of which are hereby incorporated by reference in its entirety). By directing an antisense molecule to the donor splice site, consistent and efficient exon 23 skipping was induced in the dystrophin mRNA within 6 hours of treatment of the cultured cells. Wilton et al. also describe targeting the acceptor region of the mouse dystrophin pre-mRNA with longer antisense oligonucleotides. While the first antisense oligonucleotide directed at the intron 23 donor splice site induced consistent exon skipping in primary cultured myoblasts, this compound was found to be much less efficient in immortalized cell cultures expressing higher levels of dystrophin. However, with refined targeting and antisense oligonucleotide design, the efficiency of specific exon removal was increased by almost an order of magnitude (Mann, Honeyman et al. 2002; the contents of which are hereby incorporated by reference in its entirety). 
     PMOs were initially tested in quadruplicate at doses of 0.25, 0.5, 1, 2, 5 μM in mouse myoblast C2C12 cells ( FIG. 5A  and  FIG. 5C ). Variable skipping was observed in replicates with the PMO sequences and the 0.5 and 2 μM doses used. The screening was alternatively performed in H2Kbmdx cells, a myoblast dystrophic cell model, demonstrating more consistent and reliable results ( FIG. 5A  and  FIG. 5B ). 
     In tested H2Kbmdx cell cultures, PMO 28 was the best PMO at the high concentration and one of the most efficient PMOs at the low concentration (as comparable as PMOs 45, SEQ ID NO: 18 and 39, SEQ ID NO: 48) ( FIG. 5B ). 
     Preliminary In Vivo Screening of Unconjugated PMO-MSTN Sequences in Mdx Mice 
     Based on the in vitro results, PMOs 39, SEQ ID NO: 48, 44, SEQ ID NO: 17, and 45, SEQ ID NO: 18 were selected for this study. PMO 124 was used as a control. An optimal dose of 3 nmoles (equal to 18×10 14  molecules) of PMO 124 were injected into each Tibialis anterior (TA) muscle of 8 week-old mdx mice. The amounts of the other PMOs were normalised to the same number of molecules of PMO 124 injected. Both TA muscles of 2 mice were injected with each PMO (n=4 per group) in a final volume of 25 μl (diluted in saline). Muscles were harvested 2 weeks after the injection. The results are illustrated in  FIG. 6A ,  FIG. 6B  and  FIG. 6C . 
     Calculation of PMO Doses:
         a) PMO 39, SEQ ID NO: 48 (18 mer)=18.5 μg (2 mice, 4 TAs)   b) PMO 44, SEQ ID NO: 17 (25 mer)=25.4 μg (2 mice, 4 TAs)   c) PMO 45, SEQ ID NO: 18 (25 mer)=25.5 μg (2 mice, 4 TAs)   d) PMO 124 (28 mer)=28.8 μg (2 mice, 4 TAs)       

     These amounts in μg correspond to 18×10 14  molecules per each PMO. 
     All PMOs tested were biologically active in vivo. The skipping efficiency was highest and lowest in PMO 124 and 45, SEQ ID NO: 18 treated muscles, respectively ( FIG. 6C ). However, such efficiencies did not correlate with an increase in muscle weight. Muscles treated with PMO 45, SEQ ID NO: 18 were heavier than untreated or treated muscles with PMO 124 or 44, SEQ ID NO: 17 although the differences were not significant ( FIG. 6B ). 
     Systemic Injection of PMOs in Mdx Mice 
     PMOs 39, SEQ ID NO: 48, 44, SEQ ID NO: 17, 45, SEQ ID NO: 18, and 124 were also examined for systemic skipping efficacy. The screening was performed through tail vein intravenous injection in 8 week-old mdx mice. PMO 124 was used as a control and at the dose of 200 mg/kg (equal to 12.53×10 18  molecules or 20.8 μmoles) diluted in 200 μl saline. The amount of the other PMOs was normalized to the number of molecules of PMO 124 injected. Three mice per group were used. Muscles were harvested 2 weeks after the injection, including the diaphragm—DIA, the extensor digitorum longus—EDL, the gastrocnemius—GAS, the soleus—SOL, and the tibialis anterior—TA. Results are illustrated in  FIG. 7A ,  FIG. 7B ,  FIG. 7C  and  FIG. 7D . 
     Calculation of PMO Doses:
         a) PMO 124 (28 mer)=200 mg/kg (3 mice)   b) PMO 45, SEQ ID NO: 18 (25 mer)=176.2 μg (3 mice)   c) PMO 44, SEQ ID NO: 17 (25 mer)=176.8 μg (3 mice)   d) PMO 39, SEQ ID NO: 48 (28 mer)=128.6 μg (3 mice)   These amounts in μg correspond to 12.53×10 18  molecules (20.8 μmoles) per each PMO.       

     The skipping results were variable among muscles collected from a single mouse and among the same types of muscles from different mice ( FIG. 7A  and  FIG. 7B ). However, all PMOs were biologically active in dystrophic muscles after a single IV injection. GAS and TA showed a trend of increase in weight (normalised to final body weight;  FIG. 7D ) after being injected with PMO 45, SEQ ID NO: 18 or 124, compared to type-matched muscles of saline-injected mice. 
     In Vivo Screening of B Peptide-Conjugated PMOs in C57 Mice 
     PMO D30 (SEQ ID NO: 16), PMO39 (SEQ ID NO: 48) and PMO45 (SEQ ID NO: 18) selected from previous in vitro and in vivo screening were conjugated to B peptide (RAhxRRBRRAhxRRBRAhxB; SEQ ID No: 3499 and AhxB linker moiety at the peptide carboxy terminus) at the 3′-end of the PMO and delivered by systemic tail vein injection, weekly, for 14 weeks. B peptide conjugated PMO, also referred to hereafter as BPMO, was performed in 12-week old C57 mice, 10 mice per group. Two doses were tested at 10 or 20 mg/kg. After the last injection, the force of forelimbs was measured by gripstrength test ( FIG. 9A  and  FIG. 9B ). The maximal force of TA muscles of mice treated with 10 mg/kg BPMOs were measured by in situ electrophysiology ( FIG. 9C ). The heart, DIA and 4 skeletal muscles (EDL, GAS, SOL, TA) were harvested for assessment of muscle mass and myostatin exon skipping. 
     Some of the mice in the BPMO-39 and BPMO-D30 treated groups at 20 mg/kg did not receive IV injection during the last 4-6 weeks as the tail vein was hardly visible. These mice were injected by IP instead. In BPMO-39, 20 mg/kg treated group, two mice died during the study. 
     Results: 
     1) Increase in body and muscle mass: the body weight of mice in the BPMO-39 treated group (10 or 20 mg/kg) was significantly increased compared with the weight of both saline and scramble BPMO injected animals ( FIG. 8A  and  FIG. 8C ). BPMO-D30 induced a very efficient bodyweight increase when used at 20 mg/kg ( FIG. 8C ). Variability in muscle mass (normalized against the initial body weight) was observed depending on the dosage administered and muscle considered ( FIG. 8B  and  FIG. 8D ). BPMO-39 showed the most consistent muscle increase in TA (10 or 20 mg/kg treatment;  FIG. 8B  and  FIG. 8D ) and GAS (10 mg/kg treatment;  FIG. 8B ) while BPMO-D30 or −45 induced mass increase in TA (10 mg/kg treatment;  FIG. 8B ) or GAS (20 mg/kg treatment;  FIG. 8D ). In the DIA of 20 mg/kg treated mice all of the tested BPMOs induced a significant muscle weight gain ( FIG. 8D ). The IP delivery route used in the last few injections may have had an influence on this result. 
     2) Gripstrength analysis: Measurement of the forelimb force was performed in mice treated with both BPMO dosages ( FIG. 9A  and  FIG. 9B ). BPMO-39 was the only candidate showing enhanced muscle strength compared with saline group, and only at 10 mg/kg treatment ( FIG. 9A ). The scramble BPMO unexpectedly and unexplainably increased the forelimb strength of treated mice significantly different compared to the saline treated mice at both 10 and 20 mg/kg doses ( FIG. 9A  and  FIG. 9B ). 
     3) In situ muscle physiology test: The TAs of mice treated with 10 mg/kg BPMOs were analyzed using an electrophysiology assessment. BPMO-D30 significantly increased the generated maximal and specific forces compared to the scramble PMO and the other tested BPMOs ( FIG. 9C ). 
     4) Exon skipping quantification: The myostatin skipping efficiency of DIA ( FIG. 10A  and  FIG. 10B ) and TA ( FIG. 10C  and  FIG. 10D ) muscles was analyzed. The skipping levels in 20 mg/kg treated muscles were 3-4 fold higher than the levels in 10 mg/kg treated muscles ( FIG. 10B  and  FIG. 10D ). BPMO-D30 and −45 were significantly more efficient than BPMO-39 at 20 mg/kg dose (DIA,  FIG. 10B  and TA,  FIG. 10D ) or 10 mg/kg dose (TA,  FIG. 10D ) used. 
     Provisional results of in vivo screening: BPMO-D30 and BPMO-45 were the most effective molecules taking in account the general effect on muscle weight, strength and exon skipping efficiency. Histological analysis will be performed (as possible data on the cross sectional analysis of myofibres). 
     Example 25 BPMO-Induced Dual Exon Skipping: Combination Myostatin and Dystrophin Treatment 
     Rescue of dystrophin reading frame+knockdown of myostatin in young dystrophic mice. 
     PMO M23D (SEQ ID NO. 937) was conjugated to B peptide (RAhxRRBRRAhxRRBRAhxB; SEQ ID No: 3499 and AhxB linker moiety at the peptide carboxy terminus) at the 3′-end of the PMO and was named BPMO-M23D. BPMO-M23D (10 mg/kg) and/or BPMO-MSTN (D30, 10 mg/kg) were diluted in 200 μl saline and injected through the tail vein of 6 week-old mdx mice or C57BL10 mice. The injection was repeated weekly for 10 weeks. Ten mice were used for each treatment. Details of 5 groups of mice as follow:
         a) C57BL10 mice+Saline (positive control)   b) Mdx mice+Saline (negative control)   c) Mdx mice+BPMO-M23D, SEQ ID NO: 937 (10 mg/kg)   d) Mdx mice+BPMO-M23D, SEQ ID NO: 937 (10 mg/kg) &amp; BPMO-MSTN, SEQ ID NO: 16 (10 mg/kg)   e) Mdx mice+BPMO-MSTN, SEQ ID NO: 16 (10 mg/kg)       

     Results: 
     After 12 weeks of treatment no significant increase in bodyweight was observed in treated mdx mice compared with saline injected animals ( FIG. 11A ). The grip strength analysis measuring the forelimb force revealed that injection of BPMO-M23D induced a significant increase in force compared to that of mdx mice while co-injection of BPMO-M23D and BPMO-MSTN normalized the strength to that of C57 mice ( FIG. 11B ). BPMO-MSTN treatment alone did not modify the muscle strength of treated mice compared to saline injected mdx mice ( FIG. 11B ). The grip strength test reported above was further conducted as follows. The tests were performed in 3 consecutive days (following activity cage assessment). In each test, the values of 5 reads/mouse were recorded. Each was the highest value of the forelimb force measured within 30 sec, with 30 sec interval between 2 reads. Data are shown as a total of 15 reads/mouse ( FIG. 18A ) or as 3×average of 5 reads/mouse/test ( FIG. 18B ), or as 3×highest value of 5 reads/mouse/test ( FIG. 18C ). Statistical analysis was by one-way ANOVA &amp; Bonferroni post-hoc test (n=10 per group); error bars represent the S.E.M. 
     BPMO-M23D treatment alone or in combination with BPMO-MSTN induced a very efficient dystrophin exon skipping achieving 70-80% of dystrophin reframing in all muscles analysed, with an exception of about 25% skipping in the heart ( FIG. 12A ). Treatment with BPMO-M23D in combination with BPMO-MSTN resulted in greater DMD exon skipping efficiency than treatment with the BPMO-M23D alone. Restoration of dystrophin protein was subsequently confirmed by Western blot analysis, with expression in skeletal muscles ranging between 30-100% the level of C57 mice ( FIG. 12B ). Dystrophin expression was reconfirmed by immunohistochemistry. Myostatin exon 2 skipping was also efficient in mice that had received the dual treatment, with average skipping in all examined muscles about 55% ( FIG. 12C ). 
     Further histological analyses were performed in the harvested muscles to study the effect of the treatments on myofibre hypertrophy and regeneration. The number and diameter of myofibres were investigated in addition with the frequency of centrally nucleated fibres. The therapeutic benefit in EDL, GAS, SOL and TA muscles has been assessed. Results from TA fibre analysis are reported as representative ( FIG. 13A  and  FIG. 13B ). The treatment with BPMO-MSTN alone did not modify the dystrophic phenotype whereas BPMO-M23D and BPMO-M23D+BPMO-D30 treatments partially ameliorated the pathology with a decrease in the variability of myofibre cross sectional area ( FIG. 13A ) and in the presence of centrally nucleated fibres compared to untreated mdx muscles ( FIG. 13B ). This effect was essentially due to the dystrophin restoration that reduced both the pseudo-hypertrophy of mdx muscles and the muscle degeneration process. 
     Rescue of Dystrophin Reading Frame+Knockdown of Myostatin in Aged Mdx Mice 
     BPMO-MSTN and BPMO-M23D was injected using identical dose regimen and route of administration as reported above) in aged (&gt;18 month old) mdx mice that recapitulate more accurately (compared to young mdx mice) the dystrophic disease observed in human. Mice were injected weekly for 10 weeks with either 10 mg/kg of BPMO-M23D (n=5) or BPMOM23D (10 mg/kg) and BPMO-MSTN (10 mg/kg) (n=5), or 20 mg/kg of scramble BPMO (n=4). One week after the last injection, mice underwent grip strength analyses to investigate the forelimb strength. TA muscles of treated mice were analysed by electrophysiology on the following week, prior to muscle collection. 
     Results: 
     Significant changes in bodyweight of treated mice (compared with scramble group) from week 7 were observed ( FIG. 14A ). The muscle mass was tested in DIA, EDL, GAS, SOL, TA and heart muscles in mice treated with scramble, BPMO-M23D, and BPMO-M23D and BPMO-MSTN ( FIG. 14B ). However, statistical analysis for body or muscle weight was not performed as scramble-injected mice died gradually and only 1 mouse survived at the end of the study. All of the mice treated with BPMO-M23D or with BPMO-M23D and BPMO-MSTN survived for the entire study. Gripstrength analysis demonstrated that mice treated with BPMO-M23D or with BPMO-M23D and BPMO-MSTN were stronger than mice treated with scramble BPMO ( FIG. 14C ). Further comparison of the maximal and specific force of TA muscles between the single and dual treatments displayed a significant improvement in resistance force against muscle-damaged lengthening contractions (eccentric contractions), with better effect seen in the combined treated group ( FIG. 14D ). 
     RT-PCRs were subsequently performed to evaluate the skipping efficiency of exon 23 of dystrophin that showed substantial levels of dystrophin reframing in all muscles ( FIG. 15A ). The addition of BPMO-MSTN increased the skipping efficiency of BPMO-M23D consistently as observed in young mdx mice ( FIG. 15B ). Results of dystrophin exon skipping correlated with a significant increase in protein expression in all muscles analysed ( FIG. 16A ). Further, it was shown that treatment with the combination of BPMO-MSTN and BPMO-M23D increased dystrophin levels over treatment with M23D alone ( FIG. 16B ). 
     Myostatin exon 2 skipping in all muscles harvested was evaluated by RT-PCR ( FIG. 17A ). The level of skipping varied between 5% and 40% depending on the muscle type analyzed. The average value obtained pulling together the results of all the muscles was about 20% ( FIG. 17B ). 
     It is believed that the disclosure set forth above encompasses at least one distinct invention with independent utility. While the invention has been disclosed in the exemplary forms, the specific embodiments thereof as disclosed and illustrated herein are not to be considered in a limiting sense as numerous variations are possible. Equivalent changes, modifications and variations of various embodiments, materials, compositions and methods may be made within the scope of the present invention, with substantially similar results. The subject matter of the inventions includes all novel and non-obvious combinations and subcombinations of the various elements, features, functions and/or properties disclosed herein. 
     Benefits, other advantages, and solutions to problems have been described herein with regard to specific embodiments. However, the benefits, advantages, solutions to problems, and any element or combination of elements that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as critical, required, or essential features or elements of any or all the claims of the invention. Many changes and modifications within the scope of the instant invention includes all such modifications. Corresponding structures, materials, acts, and equivalents of all elements in the claims below are intended to include any structure, material, or acts performing the functions in combination with other claim elements as specifically claimed. The scope of the invention should be determined by the appended claims and their legal equivalents, rather than by the examples given above. 
     
       
         
           
               
             
               
                 TABLE 7 
               
             
            
               
                   
               
               
                 Sequence Listing 
               
            
           
           
               
               
            
               
                 SEQ 
                   
               
               
                 ID 
               
               
                 NO: 
                 SEQUENCE 
               
               
                   
               
            
           
           
               
               
            
               
                 1 
                 agcaacttttcttttcttattcatttatagctgattttctaatgcaagtggatggaaaacccaaatgttgctt 
               
               
                   
                 ctttaaatttagctctaaaatacaatacaataaagtagtaaaggcccaactatggatatatttgagaccc 
               
               
                   
                 gtcgagactcctacaacagtgtttgtgcaaatcctgagactcatcaaacctatgaaagacggtacaag 
               
               
                   
                 gtatactggaatccgatctctgaaacttgacatgaacccaggcactggtatttggcagagcattgatgt 
               
               
                   
                 gaagacagtgttgcaaaattggctcaaacaacctgaatccaacttaggcattgaaataaaagctttagat 
               
               
                   
                 gagaatggtcatgatcttgctgtaaccttcccaggaccaggagaagatgggctggtaagtgataactga 
               
               
                   
                 aaataacattataat 
               
               
                   
               
               
                 2 
                 cttttcttttcttattcatttatagctgattttctaatgcaagtggatgg 
               
               
                   
               
               
                 3 
                 accttcccaggaccaggagaagatgggctg/gtaagtgataactgaaaataacattataat 
               
               
                   
               
               
                 4 
                 gccagacctatttgactggaatagtgtggtttgccagcagtcagccacacaacgactggaac 
               
               
                   
                 atgcattcaacatcgccagatatcaattaggcatagagaaactactcgatcctgaag 
               
               
                   
               
               
                 5 
                 atgttgataccacctatccagataagaagtccatcttaatgtacatcacatcactcttccaagtttt 
               
               
                   
                 gcctcaacaagtgagcattgaagccatccaggaagtggaaatgttgccaaggccacctaaag 
               
               
                   
                 tgactaaagaagaacattttcagttacatcatcaaatgcactattctcaacag 
               
               
                   
               
               
                 6 
                 atcacggtcagtctagcacagggatatgagagaacttcttcccctaagcctcgattcaagagct 
               
               
                   
                 atgcctacacacaggctgcttatgtcaccacctctgaccctacacggagcccatttccttcacag 
               
               
                   
               
               
                 7 
                 gccatagagcgagaaaaagctgagaagttcagaaaactgcaagatgccagcagatcagctca 
               
               
                   
                 ggccctggtggaacagatggtgaatg 
               
               
                   
               
               
                 8 
                 gctttacaaagttctctgcaagagcaacaaagtggcctatactatctcagcaccactgtgaaaga 
               
               
                   
                 gatgtcgaagaaagcgccctctgaaattagccggaaatatcaatcagaatttgaagaaattgag 
               
               
                   
                 ggacgctggaagaagctctcctcccagctggttgagcattgtcaaaagctagaggagcaaatga 
               
               
                   
                 ataaactccgaaaaattcag 
               
               
                   
               
               
                 9 
                 gcgatttgacagatctgttgagaaatggcggcgttttcattatgatataaagatatttaatcagtggct 
               
               
                   
                 aacagaagctgaacagtttctcagaaagacacaaattcctgagaattgggaacatgctaaatacaa 
               
               
                   
                 atggtatcttaag 
               
               
                   
               
               
                 10 
                 gaactccaggatggcattgggcagcggcaaactgttgtcagaacattgaatgcaactggggaaga 
               
               
                   
                 aataattcagcaatcctcaaaaacagatgccagtattctacaggaaaaattgggaagcctgaatctg 
               
               
                   
                 cggtggcaggaggtctgcaaacagctgtcagacagaaaaaagag 
               
               
                   
               
               
                 11 
                 aggaagttagaagatctgagctctgagtggaaggcggtaaaccgtttacttcaagagctgagggca 
               
               
                   
                 aagcagcctgacctagctcctggactgaccactattggagcct 
               
               
                   
               
               
                 12 
                 ctcctactcagactgttactctggtgacacaacctgtggttactaaggaaactgccatctccaaactag 
               
               
                   
                 aaatgccatcttccttgatgttggaggtacctgctctggcagatttcaaccgggcttggacagaactta 
               
               
                   
                 ccgactggctttctctgcttgatcaagttataaaatcacagagggtgatggtgggtgaccttgaggata 
               
               
                   
                 tcaacgagatgatcatcaagcagaag 
               
               
                   
               
               
                 13 
                 gcaacaatgcaggatttggaacagaggcgtccccagttggaagaactcattaccgctgcccaaaattt 
               
               
                   
                 gaaaaacaagaccagcaatcaagaggctagaacaatcattacggatcgaa 
               
               
                   
               
               
                 14 
                 ttgaaagaattcagaatcagtgggatgaagtacaagaacaccttcagaaccggaggcaacagttgaat 
               
               
                   
                 gaaatgttaaaggattcaacacaatggctggaagctaaggaagaagctgagcaggtcttaggacagg 
               
               
                   
                 ccagagccaagcttgagtcatggaaggagggtccctatacagtagatgcaatccaaaagaaaatcaca 
               
               
                   
                 gaaaccaag 
               
               
                   
               
               
                 15 
                 ggtgagtgagcgagaggctgctttggaagaaactcatagattactgcaacagttccccctggacctgga 
               
               
                   
                 aaagtttcttgcctggcttacagaagctgaaacaactgccaatgtcctacaggatgctacccgtaaggaaa 
               
               
                   
                 ggctcctagaagactccaagggagtaaaagagctgatgaaacaatggcaa 
               
               
                   
               
               
                 16 
                 cagcccatcttctcctggtcctgggaaggt 
               
               
                   
               
               
                 17 
                 ccagcccatcttctcctggtcctgg 
               
               
                   
               
               
                 18 
                 cacttaccagcccatcttctcctgg 
               
               
                   
               
               
                 19 
                 ccatccgcttgcattagaaagtcagc 
               
               
                   
               
               
                 20 
                 gcattagaaaatcagctataaatg 
               
               
                   
               
               
                 21 
                 ccacttgcattagaaaatcagc 
               
               
                   
               
               
                 22 
                 cttgcattagaaaatcagctataaa 
               
               
                   
               
               
                 23 
                 cacttgcattagaaaatcagctata 
               
               
                   
               
               
                 24 
                 ccacttgcattagaaaatcagctat 
               
               
                   
               
               
                 25 
                 tccacttgcattagaaaatcagcta 
               
               
                   
               
               
                 26 
                 atccacttgcattagaaaatcagct 
               
               
                   
               
               
                 27 
                 catccacttgcattagaaaatcagc 
               
               
                   
               
               
                 28 
                 ttattttcagttatcacttaccagc 
               
               
                   
               
               
                 29 
                 ttttcagttatcacttaccagccca 
               
               
                   
               
               
                 30 
                 tcagttatcacttaccagcccatct 
               
               
                   
               
               
                 31 
                 gttatcacttaccagcccatcttct 
               
               
                   
               
               
                 32 
                 atcacttaccagcccatcttctcct 
               
               
                   
               
               
                 33 
                 acttaccagcccatcttctcctggt 
               
               
                   
               
               
                 34 
                 taccagcccatcttctcctggtcct 
               
               
                   
               
               
                 35 
                 atgttattttcagttatcacttacc 
               
               
                   
               
               
                 36 
                 tgttattttcagttatcacttacca 
               
               
                   
               
               
                 37 
                 gttattttcagttatcacttaccag 
               
               
                   
               
               
                 38 
                 tattttcagttatcacttaccagcc 
               
               
                   
               
               
                 39 
                 attttcagttatcacttaccagccc 
               
               
                   
               
               
                 40 
                 tttcagttatcacttaccagcccat 
               
               
                   
               
               
                 41 
                 ttcagttatcacttaccagcccatc 
               
               
                   
               
               
                 42 
                 cagttatcacttaccagcccatctt 
               
               
                   
               
               
                 43 
                 agttatcacttaccagcccatcttc 
               
               
                   
               
               
                 44 
                 cagcccatcttctcctggtcctgggaaggt 
               
               
                   
               
               
                 45 
                 cagcccatcttctcctggtc 
               
               
                   
               
               
                 46 
                 tctcctggtcctgggaaggt 
               
               
                   
               
               
                 47 
                 ctgggaaggttacagcaaga 
               
               
                   
               
               
                 48 
                 cagcccatcttctcctgg 
               
               
                   
               
               
                 49 
                 gcccatcttctcctggtcctggg 
               
               
                   
               
               
                 50 
                 tttaaagaagcaacatttgggtttt 
               
               
                   
               
               
                 51 
                 tattttagagctaaatttaaagaag 
               
               
                   
               
               
                 52 
                 tactttattgtattgtattttagag 
               
               
                   
               
               
                 53 
                 tagttgggcctttactactttattg 
               
               
                   
               
               
                 54 
                 tctcaaatatatccatagttgggcc 
               
               
                   
               
               
                 55 
                 acgggtctcaaatatatccatagtt 
               
               
                   
               
               
                 56 
                 gttgtaggagtctcgacgggtctcaaatat 
               
               
                   
               
               
                 57 
                 acactgttgtaggagtctcgacggg 
               
               
                   
               
               
                 58 
                 taggtttgatgagtctcaggatttg 
               
               
                   
               
               
                 59 
                 ccgtctttcataggtttgatgagtc 
               
               
                   
               
               
                 60 
                 cagtataccttgtaccgtctttcataggtt 
               
               
                   
               
               
                 61 
                 gggttcatgtcaagtttcagagatc 
               
               
                   
               
               
                 62 
                 aataccagtgcctgggttcatgtcaagttt 
               
               
                   
               
               
                 63 
                 aaataccagtgcctgggttcatgtc 
               
               
                   
               
               
                 64 
                 tctgccaaataccagtgcctgggtt 
               
               
                   
               
               
                 65 
                 tcttcacatcaatgctctgccaaat 
               
               
                   
               
               
                 66 
                 caggttgtttgagccaattttgcaa 
               
               
                   
               
               
                 67 
                 tgcctaagttggattcaggttgttt 
               
               
                   
               
               
                 68 
                 aagcttttatttcaatgcctaagtt 
               
               
                   
               
               
                 69 
                 gaccattctcatctaaagcttttat 
               
               
                   
               
               
                 70 
                 ttacagcaagatcatgaccattctc 
               
               
                   
               
               
                 71 
                 yyagyyyaxyxxyxyyxggxyyxgg 
               
               
                   
               
               
                 72 
                 yayxxayyagyyyaxyxxyxyyxgg 
               
               
                   
               
               
                 73 
                 yyayxxgyaxxagaaaaxyagy 
               
               
                   
               
               
                 74 
                 gyattagaaaatyagytataaatg 
               
               
                   
               
               
                 75 
                 yyatyygyttgyattagaaagtyagy 
               
               
                   
               
               
                 76 
                 ctccaacatcaaggaagatggcatttctag 
               
               
                   
               
               
                 77 
                 ctccaacatc aaggaagatg gcatttctag 
               
               
                   
               
               
                 78 
                 acaucaagga agauggcauu ucuag 
               
               
                   
               
               
                 79 
                 acaucaagga agauggcauu ucuaguuugg 
               
               
                   
               
               
                 80 
                 gagcaggtac ctccaacatc aaggaa 
               
               
                   
               
               
                 81 
                 gggauccagu auacuuacag gcucc 
               
               
                   
               
               
                 82 
                 cttacaggct ccaatagtgg tcagt 
               
               
                   
               
               
                 83 
                 cctccggttc tgaaggtgtt cttgtac 
               
               
                   
               
               
                 84 
                 gttgcctccg gttctgaagg tgttc 
               
               
                   
               
               
                 85 
                 caatgccatc ctggagttcc tg 
               
               
                   
               
               
                 86 
                 gauagguggu aucaacaucu guaa 
               
               
                   
               
               
                 87 
                 gauagguggu aucaacaucu g 
               
               
                   
               
               
                 88 
                 gauagguggu aucaacaucu guaag 
               
               
                   
               
               
                 89 
                 ggugguauca acaucuguaa 
               
               
                   
               
               
                 90 
                 guaucaacau cuguaagcac 
               
               
                   
               
               
                 91 
                 ugcauguucc agucguugug ugg 
               
               
                   
               
               
                 92 
                 cacuauucca gucaaauagg ucugg 
               
               
                   
               
               
                 93 
                 auuuaccaac cuucaggauc gagua 
               
               
                   
               
               
                 94 
                 ggccuaaaac acauacacau a 
               
               
                   
               
               
                 95 
                 cauuuuugac cuacaugugg 
               
               
                   
               
               
                 96 
                 uuugaccuac auguggaaag 
               
               
                   
               
               
                 97 
                 uacauuuuug accuacaugu ggaaag 
               
               
                   
               
               
                 98 
                 auuuuugacc uacaugggaa ag 
               
               
                   
               
               
                 99 
                 uacgaguuga uugucggacc cag 
               
               
                   
               
               
                 100 
                 guggucuccu uaccuaugac ugugg 
               
               
                   
               
               
                 101 
                 ggucuccuua ccuauga 
               
               
                   
               
               
                 102 
                 ugucucagua aucuucuuac cuau 
               
               
                   
               
               
                 103 
                 ucuuaccuau gacuauggau gaga 
               
               
                   
               
               
                 104 
                 gcaugaacuc uuguggaucc 
               
               
                   
               
               
                 105 
                 ccaggguacu acuuacauua 
               
               
                   
               
               
                 106 
                 aucguguguc acagcaucca g 
               
               
                   
               
               
                 107 
                 uguucagggc augaacucuu guggauccuu 
               
               
                   
               
               
                 108 
                 uaggaggcgc cucccauccu guaggucacu g 
               
               
                   
               
               
                 109 
                 aggucuagga ggcgccuccc auccuguagg u 
               
               
                   
               
               
                 110 
                 gcgccuccca uccuguaggu cacug 
               
               
                   
               
               
                 111 
                 cuucgaggag gucuaggagg cgccuc 
               
               
                   
               
               
                 112 
                 cucccauccu guaggucacu g 
               
               
                   
               
               
                 113 
                 uaccaguuuu ugcccuguca gg 
               
               
                   
               
               
                 114 
                 ucaauaugcu gcuucccaaa cugaaa 
               
               
                   
               
               
                 115 
                 cuaggaggcg ccucccaucc uguag 
               
               
                   
               
               
                 116 
                 uuaugauuuc caucuacgau gucaguacuu c 
               
               
                   
               
               
                 117 
                 cuuaccugcc aguggaggau uauauuccaa a 
               
               
                   
               
               
                 118 
                 caucaggauu cuuaccugcc agugg 
               
               
                   
               
               
                 119 
                 cgaugucagu acuuccaaua uucac 
               
               
                   
               
               
                 120 
                 accauucauc aggauucu 
               
               
                   
               
               
                 121 
                 accugccagu ggaggauu 
               
               
                   
               
               
                 122 
                 ccaauauuca cuaaaucaac cuguuaa 
               
               
                   
               
               
                 123 
                 caggauuguu accugccagu ggaggauuau 
               
               
                   
               
               
                 124 
                 acgaugucag uacuuccaau auucacuaaa u 
               
               
                   
               
               
                 125 
                 auuuccaucu acgaugucag uacuuccaau a 
               
               
                   
               
               
                 126 
                 caggagcuuc caaaugcugc a 
               
               
                   
               
               
                 127 
                 cuugucuuca ggagcuucca aaugcugca 
               
               
                   
               
               
                 128 
                 uccucagcag aaagaagcca cg 
               
               
                   
               
               
                 129 
                 uuagaaaucu cuccuugugc 
               
               
                   
               
               
                 130 
                 uaaauugggu guuacacaau 
               
               
                   
               
               
                 131 
                 cccugaggca uucccaucuu gaau 
               
               
                   
               
               
                 132 
                 aggacuuacu ugcuuuguuu 
               
               
                   
               
               
                 133 
                 cuugaauuua ggagauucau cug 
               
               
                   
               
               
                 134 
                 caucuucuga uaauuuuccu guu 
               
               
                   
               
               
                 135 
                 ucuucuguuu uuguuagcca guca 
               
               
                   
               
               
                 136 
                 ucuauguaaa cugaaaauuu 
               
               
                   
               
               
                 137 
                 uucuggagau ccauuaaaac 
               
               
                   
               
               
                 138 
                 cagcaguugc gugaucucca cuag 
               
               
                   
               
               
                 139 
                 uucaucaacu accaccacca u 
               
               
                   
               
               
                 140 
                 cuaagcaaaa uaaucugacc uuaag 
               
               
                   
               
               
                 141 
                 cuuguaaaag aacccagcgg ucuucugu 
               
               
                   
               
               
                 142 
                 caucuacaga uguuugccca uc 
               
               
                   
               
               
                 143 
                 gaaggauguc uuguaaaaga acc 
               
               
                   
               
               
                 144 
                 accuguucuu caguaagacg 
               
               
                   
               
               
                 145 
                 caugacacac cuguucuuca guaa 
               
               
                   
               
               
                 146 
                 cauuugagaa ggaugucuug 
               
               
                   
               
               
                 147 
                 aucucccaau accuggagaa gaga 
               
               
                   
               
               
                 148 
                 gccaugcacu aaaaaggcac ugcaagacau u 
               
               
                   
               
               
                 149 
                 ucuuuaaagc caguugugug aauc 
               
               
                   
               
               
                 150 
                 uuucugaaag ccaugcacua a 
               
               
                   
               
               
                 151 
                 guacauacgg ccaguuuuug aagac 
               
               
                   
               
               
                 152 
                 cuagauccgc uuuuaaaacc uguuaaaaca a 
               
               
                   
               
               
                 153 
                 ucuuuucuag auccgcuuuu aaaaccuguu a 
               
               
                   
               
               
                 154 
                 cuagauccgc uuuuaaaacc uguua 
               
               
                   
               
               
                 155 
                 ccgucuucug ggucacugac uua 
               
               
                   
               
               
                 156 
                 cuagauccgc uuuuaaaacc uguuaa 
               
               
                   
               
               
                 157 
                 ccgcuuuuaa aaccuguuaa 
               
               
                   
               
               
                 158 
                 uggauugcuu uuucuuuucu agaucc 
               
               
                   
               
               
                 159 
                 caugcuuccg ucuucugggu cacug 
               
               
                   
               
               
                 160 
                 gaucuuguuu gagugaauac agu 
               
               
                   
               
               
                 161 
                 guuauccagc caugcuuccg uc 
               
               
                   
               
               
                 162 
                 ugauaauugg uaucacuaac cugug 
               
               
                   
               
               
                 163 
                 guaucacuaa ccugugcugu ac 
               
               
                   
               
               
                 164 
                 cugcuggcau cuugcaguu 
               
               
                   
               
               
                 165 
                 gccugagcug aucugcuggc aucuugcagu u 
               
               
                   
               
               
                 166 
                 cuggcagaau ucgauccacc ggcuguuc 
               
               
                   
               
               
                 167 
                 cagcaguagu ugucaucugc uc 
               
               
                   
               
               
                 168 
                 ugauggggug guggguugg 
               
               
                   
               
               
                 169 
                 aucugcauua acacccucua gaaag 
               
               
                   
               
               
                 170 
                 ccggcuguuc aguuguucug aggc 
               
               
                   
               
               
                 171 
                 aucugcauua acacccucua gaaagaaa 
               
               
                   
               
               
                 172 
                 gaaggagaag agauucuuac cuuacaaa 
               
               
                   
               
               
                 173 
                 auucgaucca ccggcuguuc 
               
               
                   
               
               
                 174 
                 cagcaguagu ugucaucugc 
               
               
                   
               
               
                 175 
                 gccgguugac uucauccugu gc 
               
               
                   
               
               
                 176 
                 cugcauccag gaacaugggu cc 
               
               
                   
               
               
                 177 
                 gucugcaucc aggaacaugg guc 
               
               
                   
               
               
                 178 
                 guugaagauc ugauagccgg uuga 
               
               
                   
               
               
                 179 
                 uacuuacugu cuguagcucu uucu 
               
               
                   
               
               
                 180 
                 cacucauggu cuccugauag cgca 
               
               
                   
               
               
                 181 
                 cugcaauucc ccgagucucu gc 
               
               
                   
               
               
                 182 
                 acugcuggac ccauguccug aug 
               
               
                   
               
               
                 183 
                 cuaaguugag guauggagag u 
               
               
                   
               
               
                 184 
                 uauucacaga ccugcaauuc ccc 
               
               
                   
               
               
                 185 
                 acaguggugc ugagauagua uaggcc 
               
               
                   
               
               
                 186 
                 uaggccacuu uguugcucuu gc 
               
               
                   
               
               
                 187 
                 uucagagggc gcuuucuuc 
               
               
                   
               
               
                 188 
                 gggcaggcca uuccuccuuc aga 
               
               
                   
               
               
                 189 
                 ucuucagggu uuguauguga uucu 
               
               
                   
               
               
                 190 
                 cugggcugaa uugucugaau aucacug 
               
               
                   
               
               
                 191 
                 cuguuggcac augugauccc acugag 
               
               
                   
               
               
                 192 
                 gucuauaccu guuggcacau guga 
               
               
                   
               
               
                 193 
                 ugcuuucugu aauucaucug gaguu 
               
               
                   
               
               
                 194 
                 ccuccuuucu ggcauagacc uuccac 
               
               
                   
               
               
                 195 
                 ugugucaucc auucgugcau cucug 
               
               
                   
               
               
                 196 
                 uuaaggccuc uugugcuaca ggugg 
               
               
                   
               
               
                 197 
                 ggggcucuuc uuuagcucuc uga 
               
               
                   
               
               
                 198 
                 gacuuccaaa gucuugcauu uc 
               
               
                   
               
               
                 199 
                 gccaacaugc ccaaacuucc uaag 
               
               
                   
               
               
                 200 
                 cagagauuuc cucagcuccg ccagga 
               
               
                   
               
               
                 201 
                 cuuacaucua gcaccucaga g 
               
               
                   
               
               
                 202 
                 uccgccaucu guuagggucu gugcc 
               
               
                   
               
               
                 203 
                 auuuggguua uccucugaau gucgc 
               
               
                   
               
               
                 204 
                 cauaccucuu cauguaguuc cc 
               
               
                   
               
               
                 205 
                 cauuugagcu gcguccaccu ugucug 
               
               
                   
               
               
                 206 
                 uccugggcag acuggaugcu cuguuc 
               
               
                   
               
               
                 207 
                 uugccugggc uuccugaggc auu 
               
               
                   
               
               
                 208 
                 uucugaaaua acauauaccu gugc 
               
               
                   
               
               
                 209 
                 uaguuucuga aauaacauau accug 
               
               
                   
               
               
                 210 
                 gacuugucaa aucagauugg a 
               
               
                   
               
               
                 211 
                 guuucugaaa uaacauauac cugu 
               
               
                   
               
               
                 212 
                 caccagaaau acauaccaca 
               
               
                   
               
               
                 213 
                 caaugauuua gcugugacug 
               
               
                   
               
               
                 214 
                 cgaaacuuca uggagacauc uug 
               
               
                   
               
               
                 215 
                 cuuguagacg cugcucaaaa uuggc 
               
               
                   
               
               
                 216 
                 caugcacaca ccuuugcucc 
               
               
                   
               
               
                 217 
                 ucuguacaau cugacgucca gucu 
               
               
                   
               
               
                 218 
                 gucuuuauca ccauuuccac uucagac 
               
               
                   
               
               
                 219 
                 ccgucugcuu uuucuguaca aucug 
               
               
                   
               
               
                 220 
                 uccauaucug uagcugccag cc 
               
               
                   
               
               
                 221 
                 ccaggcaacu ucagaaucca aau 
               
               
                   
               
               
                 222 
                 uuucuguuac cugaaaagaa uuauaaugaa 
               
               
                   
               
               
                 223 
                 cauucauuuc cuuucgcauc uuacg 
               
               
                   
               
               
                 224 
                 ugaucucuuu gucaauucca uaucug 
               
               
                   
               
               
                 225 
                 uucagugaua uagguuuuac cuuuccccag 
               
               
                   
               
               
                 226 
                 cuguagcugc cagccauucu gucaag 
               
               
                   
               
               
                 227 
                 ucuucugcuc gggaggugac a 
               
               
                   
               
               
                 228 
                 ccaguuacua uucagaagac 
               
               
                   
               
               
                 229 
                 ucuucaggug caccuucugu 
               
               
                   
               
               
                 230 
                 ugugaugugg uccacauucu gguca 
               
               
                   
               
               
                 231 
                 ccauguguuu cugguauucc 
               
               
                   
               
               
                 232 
                 cguguagagu ccaccuuugg gcgua 
               
               
                   
               
               
                 233 
                 uacuaauuuc cugcaguggu cacc 
               
               
                   
               
               
                 234 
                 uucuguguga aauggcugca aauc 
               
               
                   
               
               
                 235 
                 ccuucaaagg aauggaggcc 
               
               
                   
               
               
                 236 
                 ugcugaauuu cagccuccag ugguu 
               
               
                   
               
               
                 237 
                 ugaagucuuc cucuuucaga uucac 
               
               
                   
               
               
                 238 
                 cuggcuuucu cucaucugug auuc 
               
               
                   
               
               
                 239 
                 guuguaaguu gucuccucuu 
               
               
                   
               
               
                 240 
                 uugucuguaa cagcugcugu 
               
               
                   
               
               
                 241 
                 gcucuaauac cuugagagca 
               
               
                   
               
               
                 242 
                 cuuugagacc ucaaauccug uu 
               
               
                   
               
               
                 243 
                 cuuuauuuuc cuuucaucuc ugggc 
               
               
                   
               
               
                 244 
                 aucguuucuu cacggacagu gugcugg 
               
               
                   
               
               
                 245 
                 gggcuuguga gacaugagug auuu 
               
               
                   
               
               
                 246 
                 accuucagag gacuccucuu gc 
               
               
                   
               
               
                 247 
                 uauguguuac cuacccuugu cgguc 
               
               
                   
               
               
                 248 
                 ggagagagcu uccuguagcu 
               
               
                   
               
               
                 249 
                 ucacccuuuc cacaggcguu gca 
               
               
                   
               
               
                 250 
                 uuugugucuu ucugagaaac 
               
               
                   
               
               
                 251 
                 aaagacuuac cuuaagauac 
               
               
                   
               
               
                 252 
                 aucugucaaa ucgccugcag 
               
               
                   
               
               
                 253 
                 uuaccuugac uugcucaagc 
               
               
                   
               
               
                 254 
                 uccagguuca agugggauac 
               
               
                   
               
               
                 255 
                 gcucuucugg gcuuauggga gcacu 
               
               
                   
               
               
                 256 
                 accuuuaucc acuggagauu ugucugc 
               
               
                   
               
               
                 257 
                 uuccaccagu aacugaaaca g 
               
               
                   
               
               
                 258 
                 ccacucagag cucagaucuu cuaacuucc 
               
               
                   
               
               
                 259 
                 cuuccacuca gagcucagau cuucuaa 
               
               
                   
               
               
                 260 
                 accagaguaa cagucugagu aggagc 
               
               
                   
               
               
                 261 
                 cucauaccuu cugcuugaug auc 
               
               
                   
               
               
                 262 
                 uucuguccaa gcccgguuga aauc 
               
               
                   
               
               
                 263 
                 cuccaacauc aaggaagaug gcauuucuag 
               
               
                   
               
               
                 264 
                 aucauuuuuu cucauaccuu cugcu 
               
               
                   
               
               
                 265 
                 aucauuuuuu cucauaccuu cugcuaggag cuaaaa 
               
               
                   
               
               
                 266 
                 cacccaccau cacccucugu g 
               
               
                   
               
               
                 267 
                 aucaucucgu ugauauccuc aa 
               
               
                   
               
               
                 268 
                 uccugcauug uugccuguaa g 
               
               
                   
               
               
                 269 
                 uccaacuggg gacgccucug uuccaaaucc 
               
               
                   
               
               
                 270 
                 acuggggacg ccucuguucc a 
               
               
                   
               
               
                 271 
                 ccguaaugau uguucuagcc 
               
               
                   
               
               
                 272 
                 uguuaaaaaa cuuacuucga 
               
               
                   
               
               
                 273 
                 cauucaacug uugccuccgg uucug 
               
               
                   
               
               
                 274 
                 cuguugccuc cgguucugaa ggug 
               
               
                   
               
               
                 275 
                 cauucaacug uugccuccgg uucugaaggu g 
               
               
                   
               
               
                 276 
                 uacuaaccuu gguuucugug a 
               
               
                   
               
               
                 277 
                 cugaaggugu ucuuguacuu caucc 
               
               
                   
               
               
                 278 
                 uguauaggga cccuccuucc augacuc 
               
               
                   
               
               
                 279 
                 cuaaccuugg uuucugugau uuucu 
               
               
                   
               
               
                 280 
                 gguaucuuug auacuaaccu ugguuuc 
               
               
                   
               
               
                 281 
                 auucuuucaa cuagaauaaa ag 
               
               
                   
               
               
                 282 
                 gauucugaau ucuuucaacu agaau 
               
               
                   
               
               
                 283 
                 aucccacuga uucugaauuc 
               
               
                   
               
               
                 284 
                 uuggcucugg ccuguccuaa ga 
               
               
                   
               
               
                 285 
                 cucuuuucca gguucaagug ggauacuagc 
               
               
                   
               
               
                 286 
                 caagcuuuuc uuuuaguugc ugcucuuuuc c 
               
               
                   
               
               
                 287 
                 uauucuuuug uucuucuagc cuggagaaag 
               
               
                   
               
               
                 288 
                 cugcuuccuc caaccauaaa acaaauuc 
               
               
                   
               
               
                 289 
                 ccaaugccau ccuggaguuc cuguaa 
               
               
                   
               
               
                 290 
                 uccuguagaa uacuggcauc 
               
               
                   
               
               
                 291 
                 ugcagaccuc cugccaccgc agauuca 
               
               
                   
               
               
                 292 
                 cuaccucuuu uuucugucug 
               
               
                   
               
               
                 293 
                 uguuuuugag gauugcugaa 
               
               
                   
               
               
                 294 
                 gttgcctccg gttctgaagg tgttcttg 
               
               
                   
               
               
                 295 
                 ctgaaggtgt tcttgtactt catcc 
               
               
                   
               
               
                 296 
                 ctgttgcctc cggttctgaa ggtgttcttg 
               
               
                   
               
               
                 297 
                 caactgttgc ctccggttct gaaggtgttc ttg 
               
               
                   
               
               
                 298 
                 ctccggttct gaaggtgttc ttgta 
               
               
                   
               
               
                 299 
                 atttcattca actgttgcct ccggttct 
               
               
                   
               
               
                 300 
                 tgaaggtgtt cttgtacttc atccc 
               
               
                   
               
               
                 301 
                 cattcaactg ttgcctccgg ttct 
               
               
                   
               
               
                 302 
                 tgttgcctcc ggttctgaag gt 
               
               
                   
               
               
                 303 
                 gttgcctccg gttctgaagg tgttc 
               
               
                   
               
               
                 304 
                 gcctccggtt ctgaaggtgt tcttgtac 
               
               
                   
               
               
                 305 
                 cctccggttc tgaaggtgtt cttgtac 
               
               
                   
               
               
                 306 
                 ctccggttct gaaggtgttc ttgtac 
               
               
                   
               
               
                 307 
                 gcctccggtt ctgaaggtgt tcttg 
               
               
                   
               
               
                 308 
                 cagatctgtc aaatcgcctg cagg 
               
               
                   
               
               
                 309 
                 caacagatct gtcaaatcgc ctgcagg 
               
               
                   
               
               
                 310 
                 ctcaacagat ctgtcaaatc gcctgcagg 
               
               
                   
               
               
                 311 
                 gtgtctttct gagaaactgt tcagc 
               
               
                   
               
               
                 312 
                 gagaaactgt tcagcttctg ttagccac 
               
               
                   
               
               
                 313 
                 gaaactgttc agcttctgtt agccactg 
               
               
                   
               
               
                 314 
                 ctgttcagct tctgttagcc actg 
               
               
                   
               
               
                 315 
                 atctgtcaaa tcgcctgcag 
               
               
                   
               
               
                 316 
                 tttgtgtctt tctgagaaac 
               
               
                   
               
               
                 317 
                 tgttcagctt ctgttagcca ctga 
               
               
                   
               
               
                 318 
                 gatctgtcaa atcgcctgca ggtaa 
               
               
                   
               
               
                 319 
                 aaactgttca gcttctgtta gccac 
               
               
                   
               
               
                 320 
                 ttgtgtcttt ctgagaaact gttca 
               
               
                   
               
               
                 321 
                 caacagatct gtcaaatcgc ctgcag 
               
               
                   
               
               
                 322 
                 cagatctgtc aaatcgcctg caggta 
               
               
                   
               
               
                 323 
                 ctgttcagct tctgttagcc actgatt 
               
               
                   
               
               
                 324 
                 gaaactgttc agcttctgtt agccactgat t 
               
               
                   
               
               
                 325 
                 agaaactgtt cagcttctgt tagcca 
               
               
                   
               
               
                 326 
                 ctgcaggtaa aagcatatgg atcaa 
               
               
                   
               
               
                 327 
                 atcgcctgca ggtaaaagca tatgg 
               
               
                   
               
               
                 328 
                 gtcaaatcgc ctgcaggtaa aagca 
               
               
                   
               
               
                 329 
                 caacagatct gtcaaatcgc ctgca 
               
               
                   
               
               
                 330 
                 tttctcaaca gatctgtcaa atcgc 
               
               
                   
               
               
                 331 
                 ccatttctca acagatctgt caaat 
               
               
                   
               
               
                 332 
                 ataatgaaaa cgccgccatt tctca 
               
               
                   
               
               
                 333 
                 aaatatcttt atatcataat gaaaa 
               
               
                   
               
               
                 334 
                 tgttagccac tgattaaata tcttt 
               
               
                   
               
               
                 335 
                 ccaattctca ggaatttgtg tcttt 
               
               
                   
               
               
                 336 
                 gtatttagca tgttcccaat tctca 
               
               
                   
               
               
                 337 
                 cttaagatac catttgtatt tagca 
               
               
                   
               
               
                 338 
                 cttaccttaa gataccattt gtatt 
               
               
                   
               
               
                 339 
                 aaagacttac cttaagatac cattt 
               
               
                   
               
               
                 340 
                 aaatcaaaga cttaccttaa gatac 
               
               
                   
               
               
                 341 
                 aaaacaaatc aaagacttac cttaa 
               
               
                   
               
               
                 342 
                 tcgaaaaaac aaatcaaaga cttac 
               
               
                   
               
               
                 343 
                 ctgtaagata ccaaaaaggc aaaac 
               
               
                   
               
               
                 344 
                 cctgtaagat accaaaaagg caaaa 
               
               
                   
               
               
                 345 
                 agttcctgta agataccaaa aaggc 
               
               
                   
               
               
                 346 
                 gagttcctgt aagataccaa aaagg 
               
               
                   
               
               
                 347 
                 cctggagttc ctgtaagata ccaaa 
               
               
                   
               
               
                 348 
                 tcctggagtt cctgtaagat accaa 
               
               
                   
               
               
                 349 
                 gccatcctgg agttcctgta agata 
               
               
                   
               
               
                 350 
                 tgccatcctg gagttcctgt aagat 
               
               
                   
               
               
                 351 
                 ccaatgccat cctggagttc ctgta 
               
               
                   
               
               
                 352 
                 cccaatgcca tcctggagtt cctgt 
               
               
                   
               
               
                 353 
                 gctgcccaat gccatcctgg agttc 
               
               
                   
               
               
                 354 
                 cgctgcccaa tgccatcctg gagtt 
               
               
                   
               
               
                 355 
                 aacagtttgc cgctgcccaa tgcca 
               
               
                   
               
               
                 356 
                 ctgacaacag tttgccgctg cccaa 
               
               
                   
               
               
                 357 
                 gttgcattca atgttctgac aacag 
               
               
                   
               
               
                 358 
                 gctgaattat ttcttcccca gttgc 
               
               
                   
               
               
                 359 
                 attatttctt ccccagttgc attca 
               
               
                   
               
               
                 360 
                 ggcatctgtt tttgaggatt gctga 
               
               
                   
               
               
                 361 
                 tttgaggatt gctgaattat ttctt 
               
               
                   
               
               
                 362 
                 aatttttcct gtagaatact ggcat 
               
               
                   
               
               
                 363 
                 atactggcat ctgtttttga ggatt 
               
               
                   
               
               
                 364 
                 accgcagatt caggcttccc aattt 
               
               
                   
               
               
                 365 
                 ctgtttgcag acctcctgcc accgc 
               
               
                   
               
               
                 366 
                 agattcaggc ttcccaattt ttcct 
               
               
                   
               
               
                 367 
                 ctcttttttc tgtctgacag ctgtt 
               
               
                   
               
               
                 368 
                 acctcctgcc accgcagatt caggc 
               
               
                   
               
               
                 369 
                 cctacctctt ttttctgtct gacag 
               
               
                   
               
               
                 370 
                 gacagctgtt tgcagacctc ctgcc 
               
               
                   
               
               
                 371 
                 gtcgccctac ctcttttttc tgtct 
               
               
                   
               
               
                 372 
                 gatctgtcgc cctacctctt ttttc 
               
               
                   
               
               
                 373 
                 tattagatct gtcgccctac ctctt 
               
               
                   
               
               
                 374 
                 attcctatta gatctgtcgc cctac 
               
               
                   
               
               
                 375 
                 agataccaaa aaggcaaaac 
               
               
                   
               
               
                 376 
                 aagataccaa aaaggcaaaa 
               
               
                   
               
               
                 377 
                 cctgtaagat accaaaaagg 
               
               
                   
               
               
                 378 
                 gagttcctgt aagataccaa 
               
               
                   
               
               
                 379 
                 tcctggagtt cctgtaagat 
               
               
                   
               
               
                 380 
                 tgccatcctg gagttcctgt 
               
               
                   
               
               
                 381 
                 cccaatgcca tcctggagtt 
               
               
                   
               
               
                 382 
                 cgctgcccaa tgccatcctg 
               
               
                   
               
               
                 383 
                 ctgacaacag tttgccgctg 
               
               
                   
               
               
                 384 
                 gttgcattca atgttctgac 
               
               
                   
               
               
                 385 
                 attatttctt ccccagttgc 
               
               
                   
               
               
                 386 
                 tttgaggatt gctgaattat 
               
               
                   
               
               
                 387 
                 atactggcat ctgtttttga 
               
               
                   
               
               
                 388 
                 aatttttcct gtagaatact 
               
               
                   
               
               
                 389 
                 agattcaggc ttcccaattt 
               
               
                   
               
               
                 390 
                 acctcctgcc accgcagatt 
               
               
                   
               
               
                 391 
                 gacagctgtt tgcagacctc 
               
               
                   
               
               
                 392 
                 ctcttttttc tgtctgacag 
               
               
                   
               
               
                 393 
                 cctacctctt ttttctgtct 
               
               
                   
               
               
                 394 
                 gtcgccctac ctcttttttc 
               
               
                   
               
               
                 395 
                 gatctgtcgc cctacctctt 
               
               
                   
               
               
                 396 
                 tattagatct gtcgccctac 
               
               
                   
               
               
                 397 
                 attcctatta gatctgtcgc 
               
               
                   
               
               
                 398 
                 gggggatttg agaaaataaa attac 
               
               
                   
               
               
                 399 
                 atttgagaaa ataaaattac cttga 
               
               
                   
               
               
                 400 
                 ctagcctgga gaaagaagaa taaaa 
               
               
                   
               
               
                 401 
                 agaaaataaa attaccttga cttgc 
               
               
                   
               
               
                 402 
                 ttcttctagc ctggagaaag aagaa 
               
               
                   
               
               
                 403 
                 ataaaattac cttgacttgc tcaag 
               
               
                   
               
               
                 404 
                 ttttgttctt ctagcctgga gaaag 
               
               
                   
               
               
                 405 
                 attaccttga cttgctcaag ctttt 
               
               
                   
               
               
                 406 
                 tattcttttg ttcttctagc ctgga 
               
               
                   
               
               
                 407 
                 cttgacttgc tcaagctttt ctttt 
               
               
                   
               
               
                 408 
                 caagatattc ttttgttctt ctagc 
               
               
                   
               
               
                 409 
                 cttttagttg ctgctctttt ccagg 
               
               
                   
               
               
                 410 
                 ccaggttcaa gtgggatact agcaa 
               
               
                   
               
               
                 411 
                 atctctttga aattctgaca agata 
               
               
                   
               
               
                 412 
                 agcaatgtta tctgcttcct ccaac 
               
               
                   
               
               
                 413 
                 aacaaattca tttaaatctc tttga 
               
               
                   
               
               
                 414 
                 ccaaccataa aacaaattca tttaa 
               
               
                   
               
               
                 415 
                 ttcctccaac cataaaacaa attca 
               
               
                   
               
               
                 416 
                 tttaaatctc tttgaaattc tgaca 
               
               
                   
               
               
                 417 
                 tgacaagata ttcttttgtt cttct 
               
               
                   
               
               
                 418 
                 ttcaagtggg atactagcaa tgtta 
               
               
                   
               
               
                 419 
                 agatattctt ttgttcttct agcct 
               
               
                   
               
               
                 420 
                 ctgctctttt ccaggttcaa gtggg 
               
               
                   
               
               
                 421 
                 ttcttttgtt cttctagcct ggaga 
               
               
                   
               
               
                 422 
                 cttttctttt agttgctgct ctttt 
               
               
                   
               
               
                 423 
                 ttgttcttct agcctggaga aagaa 
               
               
                   
               
               
                 424 
                 cttctagcct ggagaaagaa gaata 
               
               
                   
               
               
                 425 
                 agcctggaga aagaagaata aaatt 
               
               
                   
               
               
                 426 
                 ctggagaaag aagaataaaa ttgtt 
               
               
                   
               
               
                 427 
                 gaaagaagaa taaaattgtt 
               
               
                   
               
               
                 428 
                 ggagaaagaa gaataaaatt 
               
               
                   
               
               
                 429 
                 agcctggaga aagaagaata 
               
               
                   
               
               
                 430 
                 cttctagcct ggagaaagaa 
               
               
                   
               
               
                 431 
                 ttgttcttct agcctggaga 
               
               
                   
               
               
                 432 
                 ttcttttgtt cttctagcct 
               
               
                   
               
               
                 433 
                 tgacaagata ttcttttgtt 
               
               
                   
               
               
                 434 
                 atctctttga aattctgaca 
               
               
                   
               
               
                 435 
                 aacaaattca tttaaatctc 
               
               
                   
               
               
                 436 
                 ttcctccaac cataaaacaa 
               
               
                   
               
               
                 437 
                 agcaatgtta tctgcttcct 
               
               
                   
               
               
                 438 
                 ttcaagtggg atactagcaa 
               
               
                   
               
               
                 439 
                 ctgctctttt ccaggttcaa 
               
               
                   
               
               
                 440 
                 cttttctttt agttgctgct 
               
               
                   
               
               
                 441 
                 cttgacttgc tcaagctttt 
               
               
                   
               
               
                 442 
                 attaccttga cttgctcaag 
               
               
                   
               
               
                 443 
                 ataaaattac cttgacttgc 
               
               
                   
               
               
                 444 
                 agaaaataaa attaccttga 
               
               
                   
               
               
                 445 
                 atttgagaaa ataaaattac 
               
               
                   
               
               
                 446 
                 gggggatttg agaaaataaa 
               
               
                   
               
               
                 447 
                 ctgaaacaga caaatgcaac aacgt 
               
               
                   
               
               
                 448 
                 agtaactgaa acagacaaat gcaac 
               
               
                   
               
               
                 449 
                 ccaccagtaa ctgaaacaga caaat 
               
               
                   
               
               
                 450 
                 ctcttccacc agtaactgaa acaga 
               
               
                   
               
               
                 451 
                 ggcaactctt ccaccagtaa ctgaa 
               
               
                   
               
               
                 452 
                 gcaggggcaa ctcttccacc agtaa 
               
               
                   
               
               
                 453 
                 ctggcgcagg ggcaactctt ccacc 
               
               
                   
               
               
                 454 
                 tttaattgtt tgagaattcc ctggc 
               
               
                   
               
               
                 455 
                 ttgtttgaga attccctggc gcagg 
               
               
                   
               
               
                 456 
                 gcacgggtcc tccagtttca tttaa 
               
               
                   
               
               
                 457 
                 tccagtttca tttaattgtt tgaga 
               
               
                   
               
               
                 458 
                 gcttatggga gcacttacaa gcacg 
               
               
                   
               
               
                 459 
                 tacaagcacg ggtcctccag tttca 
               
               
                   
               
               
                 460 
                 agtttatctt gctcttctgg gctta 
               
               
                   
               
               
                 461 
                 tctgcttgag cttattttca agttt 
               
               
                   
               
               
                 462 
                 atcttgctct tctgggctta tggga 
               
               
                   
               
               
                 463 
                 ctttatccac tggagatttg tctgc 
               
               
                   
               
               
                 464 
                 cttattttca agtttatctt gctct 
               
               
                   
               
               
                 465 
                 ctaaccttta tccactggag atttg 
               
               
                   
               
               
                 466 
                 atttgtctgc ttgagcttat tttca 
               
               
                   
               
               
                 467 
                 aatgtctaac ctttatccac tggag 
               
               
                   
               
               
                 468 
                 tggttaatgt ctaaccttta tccac 
               
               
                   
               
               
                 469 
                 agagatggtt aatgtctaac cttta 
               
               
                   
               
               
                 470 
                 acggaagaga tggttaatgt ctaac 
               
               
                   
               
               
                 471 
                 acagacaaat gcaacaacgt 
               
               
                   
               
               
                 472 
                 ctgaaacaga caaatgcaac 
               
               
                   
               
               
                 473 
                 agtaactgaa acagacaaat 
               
               
                   
               
               
                 474 
                 ccaccagtaa ctgaaacaga 
               
               
                   
               
               
                 475 
                 ctcttccacc agtaactgaa 
               
               
                   
               
               
                 476 
                 ggcaactctt ccaccagtaa 
               
               
                   
               
               
                 477 
                 ctggcgcagg ggcaactctt 
               
               
                   
               
               
                 478 
                 ttgtttgaga attccctggc 
               
               
                   
               
               
                 479 
                 tccagtttca tttaattgtt 
               
               
                   
               
               
                 480 
                 tacaagcacg ggtcctccag 
               
               
                   
               
               
                 481 
                 gcttatggga gcacttacaa 
               
               
                   
               
               
                 482 
                 atcttgctct tctgggctta 
               
               
                   
               
               
                 483 
                 cttattttca agtttatctt 
               
               
                   
               
               
                 484 
                 atttgtctgc ttgagcttat 
               
               
                   
               
               
                 485 
                 ctttatccac tggagatttg 
               
               
                   
               
               
                 486 
                 ctaaccttta tccactggag 
               
               
                   
               
               
                 487 
                 aatgtctaac ctttatccac 
               
               
                   
               
               
                 488 
                 tggttaatgt ctaaccttta 
               
               
                   
               
               
                 489 
                 agagatggtt aatgtctaac 
               
               
                   
               
               
                 490 
                 acggaagaga tggttaatgt 
               
               
                   
               
               
                 491 
                 ctgaaaggaa aatacatttt aaaaa 
               
               
                   
               
               
                 492 
                 cctgaaagga aaatacattt taaaa 
               
               
                   
               
               
                 493 
                 gaaacctgaa aggaaaatac atttt 
               
               
                   
               
               
                 494 
                 ggaaacctga aaggaaaata cattt 
               
               
                   
               
               
                 495 
                 ctctggaaac ctgaaaggaa aatac 
               
               
                   
               
               
                 496 
                 gctctggaaa cctgaaagga aaata 
               
               
                   
               
               
                 497 
                 taaagctctg gaaacctgaa aggaa 
               
               
                   
               
               
                 498 
                 gtaaagctct ggaaacctga aagga 
               
               
                   
               
               
                 499 
                 tcaggtaaag ctctggaaac ctgaa 
               
               
                   
               
               
                 500 
                 ctcaggtaaa gctctggaaa cctga 
               
               
                   
               
               
                 501 
                 gtttctcagg taaagctctg gaaac 
               
               
                   
               
               
                 502 
                 tgtttctcag gtaaagctct ggaaa 
               
               
                   
               
               
                 503 
                 aatttctcct tgtttctcag gtaaa 
               
               
                   
               
               
                 504 
                 tttgagcttc aatttctcct tgttt 
               
               
                   
               
               
                 505 
                 ttttatttga gcttcaattt ctcct 
               
               
                   
               
               
                 506 
                 aagctgccca aggtctttta tttga 
               
               
                   
               
               
                 507 
                 aggtcttcaa gctttttttc aagct 
               
               
                   
               
               
                 508 
                 ttcaagcttt ttttcaagct gccca 
               
               
                   
               
               
                 509 
                 gatgatttaa ctgctcttca aggtc 
               
               
                   
               
               
                 510 
                 ctgctcttca aggtcttcaa gcttt 
               
               
                   
               
               
                 511 
                 aggagataac cacagcagca gatga 
               
               
                   
               
               
                 512 
                 cagcagatga tttaactgct cttca 
               
               
                   
               
               
                 513 
                 atttccaact gattcctaat aggag 
               
               
                   
               
               
                 514 
                 cttggtttgg ttggttataa atttc 
               
               
                   
               
               
                 515 
                 caactgattc ctaataggag ataac 
               
               
                   
               
               
                 516 
                 cttaacgtca aatggtcctt cttgg 
               
               
                   
               
               
                 517 
                 ttggttataa atttccaact gattc 
               
               
                   
               
               
                 518 
                 cctaccttaa cgtcaaatgg tcctt 
               
               
                   
               
               
                 519 
                 tccttcttgg tttggttggt tataa 
               
               
                   
               
               
                 520 
                 agttccctac cttaacgtca aatgg 
               
               
                   
               
               
                 521 
                 caaaaagttc cctaccttaa cgtca 
               
               
                   
               
               
                 522 
                 taaagcaaaa agttccctac cttaa 
               
               
                   
               
               
                 523 
                 atatttaaag caaaaagttc cctac 
               
               
                   
               
               
                 524 
                 aggaaaatac attttaaaaa 
               
               
                   
               
               
                 525 
                 aaggaaaata cattttaaaa 
               
               
                   
               
               
                 526 
                 cctgaaagga aaatacattt 
               
               
                   
               
               
                 527 
                 ggaaacctga aaggaaaata 
               
               
                   
               
               
                 528 
                 gctctggaaa cctgaaagga 
               
               
                   
               
               
                 529 
                 gtaaagctct ggaaacctga 
               
               
                   
               
               
                 530 
                 ctcaggtaaa gctctggaaa 
               
               
                   
               
               
                 531 
                 aatttctcct tgtttctcag 
               
               
                   
               
               
                 532 
                 ttttatttga gcttcaattt 
               
               
                   
               
               
                 533 
                 aagctgccca aggtctttta 
               
               
                   
               
               
                 534 
                 ttcaagcttt ttttcaagct 
               
               
                   
               
               
                 535 
                 ctgctcttca aggtcttcaa 
               
               
                   
               
               
                 536 
                 cagcagatga tttaactgct 
               
               
                   
               
               
                 537 
                 aggagataac cacagcagca 
               
               
                   
               
               
                 538 
                 caactgattc ctaataggag 
               
               
                   
               
               
                 539 
                 ttggttataa atttccaact 
               
               
                   
               
               
                 540 
                 tccttcttgg tttggttggt 
               
               
                   
               
               
                 541 
                 cttaacgtca aatggtcctt 
               
               
                   
               
               
                 542 
                 cctaccttaa cgtcaaatgg 
               
               
                   
               
               
                 543 
                 agttccctac cttaacgtca 
               
               
                   
               
               
                 544 
                 caaaaagttc cctaccttaa 
               
               
                   
               
               
                 545 
                 taaagcaaaa agttccctac 
               
               
                   
               
               
                 546 
                 atatttaaag caaaaagttc 
               
               
                   
               
               
                 547 
                 ctggggaaaa gaacccatat agtgc 
               
               
                   
               
               
                 548 
                 tcctggggaa aagaacccat atagt 
               
               
                   
               
               
                 549 
                 gtttcctggg gaaaagaacc catat 
               
               
                   
               
               
                 550 
                 cagtttcctg gggaaaagaa cccat 
               
               
                   
               
               
                 551 
                 tttcagtttc ctggggaaaa gaacc 
               
               
                   
               
               
                 552 
                 tatttcagtt tcctggggaa aagaa 
               
               
                   
               
               
                 553 
                 tgctatttca gtttcctggg gaaaa 
               
               
                   
               
               
                 554 
                 actgctattt cagtttcctg gggaa 
               
               
                   
               
               
                 555 
                 tgaactgcta tttcagtttc ctggg 
               
               
                   
               
               
                 556 
                 cttgaactgc tatttcagtt tcctg 
               
               
                   
               
               
                 557 
                 tagcttgaac tgctatttca gtttc 
               
               
                   
               
               
                 558 
                 tttagcttga actgctattt cagtt 
               
               
                   
               
               
                 559 
                 ttccacatcc ggttgtttag cttga 
               
               
                   
               
               
                 560 
                 tgccctttag acaaaatctc ttcca 
               
               
                   
               
               
                 561 
                 tttagacaaa atctcttcca catcc 
               
               
                   
               
               
                 562 
                 gtttttcctt gtacaaatgc tgccc 
               
               
                   
               
               
                 563 
                 gtacaaatgc tgccctttag acaaa 
               
               
                   
               
               
                 564 
                 cttcactggc tgagtggctg gtttt 
               
               
                   
               
               
                 565 
                 ggctggtttt tccttgtaca aatgc 
               
               
                   
               
               
                 566 
                 attaccttca ctggctgagt ggctg 
               
               
                   
               
               
                 567 
                 gcttcattac cttcactggc tgagt 
               
               
                   
               
               
                 568 
                 aggttgcttc attaccttca ctggc 
               
               
                   
               
               
                 569 
                 gctagaggtt gcttcattac cttca 
               
               
                   
               
               
                 570 
                 atattgctag aggttgcttc attac 
               
               
                   
               
               
                 571 
                 gaaaagaacc catatagtgc 
               
               
                   
               
               
                 572 
                 gggaaaagaa cccatatagt 
               
               
                   
               
               
                 573 
                 tcctggggaa aagaacccat 
               
               
                   
               
               
                 574 
                 cagtttcctg gggaaaagaa 
               
               
                   
               
               
                 575 
                 tatttcagtt tcctggggaa 
               
               
                   
               
               
                 576 
                 actgctattt cagtttcctg 
               
               
                   
               
               
                 577 
                 cttgaactgc tatttcagtt 
               
               
                   
               
               
                 578 
                 tttagcttga actgctattt 
               
               
                   
               
               
                 579 
                 ttccacatcc ggttgtttag 
               
               
                   
               
               
                 580 
                 tttagacaaa atctcttcca 
               
               
                   
               
               
                 581 
                 gtacaaatgc tgccctttag 
               
               
                   
               
               
                 582 
                 ggctggtttt tccttgtaca 
               
               
                   
               
               
                 583 
                 cttcactggc tgagtggctg 
               
               
                   
               
               
                 584 
                 attaccttca ctggctgagt 
               
               
                   
               
               
                 585 
                 gcttcattac cttcactggc 
               
               
                   
               
               
                 586 
                 aggttgcttc attaccttca 
               
               
                   
               
               
                 587 
                 gctagaggtt gcttcattac 
               
               
                   
               
               
                 588 
                 atattgctag aggttgcttc 
               
               
                   
               
               
                 589 
                 ctttaacaga aaagcataca catta 
               
               
                   
               
               
                 590 
                 tcctctttaa cagaaaagca tacac 
               
               
                   
               
               
                 591 
                 ttcctcttta acagaaaagc ataca 
               
               
                   
               
               
                 592 
                 taacttcctc tttaacagaa aagca 
               
               
                   
               
               
                 593 
                 ctaacttcct ctttaacaga aaagc 
               
               
                   
               
               
                 594 
                 tcttctaact tcctctttaa cagaa 
               
               
                   
               
               
                 595 
                 atcttctaac ttcctcttta acaga 
               
               
                   
               
               
                 596 
                 tcagatcttc taacttcctc tttaa 
               
               
                   
               
               
                 597 
                 ctcagatctt ctaacttcct cttta 
               
               
                   
               
               
                 598 
                 agagctcaga tcttctaact tcctc 
               
               
                   
               
               
                 599 
                 cagagctcag atcttctaac ttcct 
               
               
                   
               
               
                 600 
                 cactcagagc tcagatcttc tact 
               
               
                   
               
               
                 601 
                 ccttccactc agagctcaga tcttc 
               
               
                   
               
               
                 602 
                 gtaaacggtt taccgccttc cactc 
               
               
                   
               
               
                 603 
                 ctttgccctc agctcttgaa gtaaa 
               
               
                   
               
               
                 604 
                 ccctcagctc ttgaagtaaa cggtt 
               
               
                   
               
               
                 605 
                 ccaggagcta ggtcaggctg ctttg 
               
               
                   
               
               
                 606 
                 ggtcaggctg ctttgccctc agctc 
               
               
                   
               
               
                 607 
                 aggctccaat agtggtcagt ccagg 
               
               
                   
               
               
                 608 
                 tcagtccagg agctaggtca ggctg 
               
               
                   
               
               
                 609 
                 cttacaggct ccaatagtgg tcagt 
               
               
                   
               
               
                 610 
                 gtatacttac aggctccaat agtgg 
               
               
                   
               
               
                 611 
                 atccagtata cttacaggct ccaat 
               
               
                   
               
               
                 612 
                 atgggatcca gtatacttac aggct 
               
               
                   
               
               
                 613 
                 agagaatggg atccagtata cttac 
               
               
                   
               
               
                 614 
                 acagaaaagc atacacatta 
               
               
                   
               
               
                 615 
                 tttaacagaa aagcatacac 
               
               
                   
               
               
                 616 
                 tcctctttaa cagaaaagca 
               
               
                   
               
               
                 617 
                 taacttcctc tttaacagaa 
               
               
                   
               
               
                 618 
                 tcttctaact tcctctttaa 
               
               
                   
               
               
                 619 
                 tcagatcttc taacttcctc 
               
               
                   
               
               
                 620 
                 ccttccactc agagctcaga 
               
               
                   
               
               
                 621 
                 gtaaacggtt taccgccttc 
               
               
                   
               
               
                 622 
                 ccctcagctc ttgaagtaaa 
               
               
                   
               
               
                 623 
                 ggtcaggctg ctttgccctc 
               
               
                   
               
               
                 624 
                 tcagtccagg agctaggtca 
               
               
                   
               
               
                 625 
                 aggctccaat agtggtcagt 
               
               
                   
               
               
                 626 
                 cttacaggct ccaatagtgg 
               
               
                   
               
               
                 627 
                 gtatacttac aggctccaat 
               
               
                   
               
               
                 628 
                 atccagtata cttacaggct 
               
               
                   
               
               
                 629 
                 atgggatcca gtatacttac 
               
               
                   
               
               
                 630 
                 agagaatggg atccagtata 
               
               
                   
               
               
                 631 
                 ctaaaatatt ttgggttttt gcaaaa 
               
               
                   
               
               
                 632 
                 gctaaaatat tttgggtttt tgcaaa 
               
               
                   
               
               
                 633 
                 taggagctaa aatattttgg gttttt 
               
               
                   
               
               
                 634 
                 agtaggagct aaaatatttt gggtt 
               
               
                   
               
               
                 635 
                 tgagtaggag ctaaaatatt ttggg 
               
               
                   
               
               
                 636 
                 ctgagtagga gctaaaatat tttggg 
               
               
                   
               
               
                 637 
                 cagtctgagt aggagctaaa atatt 
               
               
                   
               
               
                 638 
                 acagtctgag taggagctaa aatatt 
               
               
                   
               
               
                 639 
                 gagtaacagt ctgagtagga gctaaa 
               
               
                   
               
               
                 640 
                 cagagtaaca gtctgagtag gagct 
               
               
                   
               
               
                 641 
                 caccagagta acagtctgag taggag 
               
               
                   
               
               
                 642 
                 gtcaccagag taacagtctg agtag 
               
               
                   
               
               
                 643 
                 aaccacaggt tgtgtcacca gagtaa 
               
               
                   
               
               
                 644 
                 gttgtgtcac cagagtaaca gtctg 
               
               
                   
               
               
                 645 
                 tggcagtttc cttagtaacc acaggt 
               
               
                   
               
               
                 646 
                 atttctagtt tggagatggc agtttc 
               
               
                   
               
               
                 647 
                 ggaagatggc atttctagtt tggag 
               
               
                   
               
               
                 648 
                 catcaaggaa gatggcattt ctagtt 
               
               
                   
               
               
                 649 
                 gagcaggtac ctccaacatc aaggaa 
               
               
                   
               
               
                 650 
                 atctgccaga gcaggtacct ccaac 
               
               
                   
               
               
                 651 
                 aagttctgtc caagcccggt tgaaat 
               
               
                   
               
               
                 652 
                 cggttgaaat ctgccagagc aggtac 
               
               
                   
               
               
                 653 
                 gagaaagcca gtcggtaagt tctgtc 
               
               
                   
               
               
                 654 
                 gtcggtaagt tctgtccaag cccgg 
               
               
                   
               
               
                 655 
                 ataacttgat caagcagaga aagcca 
               
               
                   
               
               
                 656 
                 aagcagagaa agccagtcgg taagt 
               
               
                   
               
               
                 657 
                 caccctctgt gattttataa cttgat 
               
               
                   
               
               
                 658 
                 caaggtcacc caccatcacc ctctgt 
               
               
                   
               
               
                 659 
                 catcaccctc tgtgatttta taact 
               
               
                   
               
               
                 660 
                 cttctgcttg atgatcatct cgttga 
               
               
                   
               
               
                 661 
                 ccttctgctt gatgatcatc tcgttg 
               
               
                   
               
               
                 662 
                 atctcgttga tatcctcaag gtcacc 
               
               
                   
               
               
                 663 
                 tcataccttc tgcttgatga tcatct 
               
               
                   
               
               
                 664 
                 tcattttttc tcataccttc tgcttg 
               
               
                   
               
               
                 665 
                 ttttctcata ccttctgctt gatgat 
               
               
                   
               
               
                 666 
                 ttttatcatt ttttctcata ccttct 
               
               
                   
               
               
                 667 
                 ccaactttta tcattttttc tcatac 
               
               
                   
               
               
                 668 
                 atattttggg tttttgcaaa 
               
               
                   
               
               
                 669 
                 aaaatatttt gggtttttgc 
               
               
                   
               
               
                 670 
                 gagctaaaat attttgggtt 
               
               
                   
               
               
                 671 
                 agtaggagct aaaatatttt 
               
               
                   
               
               
                 672 
                 gtctgagtag gagctaaaat 
               
               
                   
               
               
                 673 
                 taacagtctg agtaggagct 
               
               
                   
               
               
                 674 
                 cagagtaaca gtctgagtag 
               
               
                   
               
               
                 675 
                 cacaggttgt gtcaccagag 
               
               
                   
               
               
                 676 
                 agtttcctta gtaaccacag 
               
               
                   
               
               
                 677 
                 tagtttggag atggcagttt 
               
               
                   
               
               
                 678 
                 ggaagatggc atttctagtt 
               
               
                   
               
               
                 679 
                 tacctccaac atcaaggaag 
               
               
                   
               
               
                 680 
                 atctgccaga gcaggtacct 
               
               
                   
               
               
                 681 
                 ccaagcccgg ttgaaatctg 
               
               
                   
               
               
                 682 
                 gtcggtaagt tctgtccaag 
               
               
                   
               
               
                 683 
                 aagcagagaa agccagtcgg 
               
               
                   
               
               
                 684 
                 ttttataact tgatcaagca 
               
               
                   
               
               
                 685 
                 catcaccctc tgtgatttta 
               
               
                   
               
               
                 686 
                 ctcaaggtca cccaccatca 
               
               
                   
               
               
                 687 
                 catctcgttg atatcctcaa 
               
               
                   
               
               
                 688 
                 cttctgcttg atgatcatct 
               
               
                   
               
               
                 689 
                 cataccttct gcttgatgat 
               
               
                   
               
               
                 690 
                 tttctcatac cttctgcttg 
               
               
                   
               
               
                 691 
                 cattttttct cataccttct 
               
               
                   
               
               
                 692 
                 tttatcattt tttctcatac 
               
               
                   
               
               
                 693 
                 caacttttat cattttttct 
               
               
                   
               
               
                 694 
                 ctgtaagaac aaatatccct tagta 
               
               
                   
               
               
                 695 
                 tgcctgtaag aacaaatatc cctta 
               
               
                   
               
               
                 696 
                 gttgcctgta agaacaaata tccct 
               
               
                   
               
               
                 697 
                 attgttgcct gtaagaacaa atatc 
               
               
                   
               
               
                 698 
                 gcattgttgc ctgtaagaac aaata 
               
               
                   
               
               
                 699 
                 cctgcattgt tgcctgtaag aacaa 
               
               
                   
               
               
                 700 
                 atcctgcatt gttgcctgta agaac 
               
               
                   
               
               
                 701 
                 caaatcctgc attgttgcct gtaag 
               
               
                   
               
               
                 702 
                 tccaaatcct gcattgttgc ctgta 
               
               
                   
               
               
                 703 
                 tgttccaaat cctgcattgt tgcct 
               
               
                   
               
               
                 704 
                 tctgttccaa atcctgcatt gttgc 
               
               
                   
               
               
                 705 
                 aactggggac gcctctgttc caaat 
               
               
                   
               
               
                 706 
                 gcctctgttc caaatcctgc attgt 
               
               
                   
               
               
                 707 
                 cagcggtaat gagttcttcc aactg 
               
               
                   
               
               
                 708 
                 cttccaactg gggacgcctc tgttc 
               
               
                   
               
               
                 709 
                 cttgtttttc aaattttggg cagcg 
               
               
                   
               
               
                 710 
                 ctagcctctt gattgctggt cttgt 
               
               
                   
               
               
                 711 
                 ttttcaaatt ttgggcagcg gtaat 
               
               
                   
               
               
                 712 
                 ttcgatccgt aatgattgtt ctagc 
               
               
                   
               
               
                 713 
                 gattgctggt cttgtttttc aaatt 
               
               
                   
               
               
                 714 
                 cttacttcga tccgtaatga ttgtt 
               
               
                   
               
               
                 715 
                 ttgttctagc ctcttgattg ctggt 
               
               
                   
               
               
                 716 
                 aaaaacttac ttcgatccgt aatga 
               
               
                   
               
               
                 717 
                 tgttaaaaaa cttacttcga tccgt 
               
               
                   
               
               
                 718 
                 atgcttgtta aaaaacttac ttcga 
               
               
                   
               
               
                 719 
                 gtcccatgct tgttaaaaaa cttac 
               
               
                   
               
               
                 720 
                 agaacaaata tcccttagta 
               
               
                   
               
               
                 721 
                 gtaagaacaa atatccctta 
               
               
                   
               
               
                 722 
                 tgcctgtaag aacaaatatc 
               
               
                   
               
               
                 723 
                 attgttgcct gtaagaacaa 
               
               
                   
               
               
                 724 
                 cctgcattgt tgcctgtaag 
               
               
                   
               
               
                 725 
                 caaatcctgc attgttgcct 
               
               
                   
               
               
                 726 
                 gcctctgttc caaatcctgc 
               
               
                   
               
               
                 727 
                 cttccaactg gggacgcctc 
               
               
                   
               
               
                 728 
                 cagcggtaat gagttcttcc 
               
               
                   
               
               
                 729 
                 ttttcaaatt ttgggcagcg 
               
               
                   
               
               
                 730 
                 gattgctggt cttgtttttc 
               
               
                   
               
               
                 731 
                 ttgttctagc ctcttgattg 
               
               
                   
               
               
                 732 
                 ttcgatccgt aatgattgtt 
               
               
                   
               
               
                 733 
                 cttacttcga tccgtaatga 
               
               
                   
               
               
                 734 
                 aaaaacttac ttcgatccgt 
               
               
                   
               
               
                 735 
                 tgttaaaaaa cttacttcga 
               
               
                   
               
               
                 736 
                 atgcttgtta aaaaacttac 
               
               
                   
               
               
                 737 
                 gtcccatgct tgttaaaaaa 
               
               
                   
               
               
                 738 
                 ctagaataaa aggaaaaata aatat 
               
               
                   
               
               
                 739 
                 aactagaata aaaggaaaaa taaat 
               
               
                   
               
               
                 740 
                 ttcaactaga ataaaaggaa aaata 
               
               
                   
               
               
                 741 
                 ctttcaacta gaataaaagg aaaaa 
               
               
                   
               
               
                 742 
                 attctttcaa ctagaataaa aggaa 
               
               
                   
               
               
                 743 
                 gaattctttc aactagaata aaagg 
               
               
                   
               
               
                 744 
                 tctgaattct ttcaactaga ataaa 
               
               
                   
               
               
                 745 
                 attctgaatt ctttcaacta gaata 
               
               
                   
               
               
                 746 
                 ctgattctga attctttcaa ctaga 
               
               
                   
               
               
                 747 
                 cactgattct gaattctttc aacta 
               
               
                   
               
               
                 748 
                 tcccactgat tctgaattct ttcaa 
               
               
                   
               
               
                 749 
                 catcccactg attctgaatt ctttc 
               
               
                   
               
               
                 750 
                 tacttcatcc cactgattct gaatt 
               
               
                   
               
               
                 751 
                 cggttctgaa ggtgttcttg tact 
               
               
                   
               
               
                 752 
                 ctgttgcctc cggttctgaa ggtgt 
               
               
                   
               
               
                 753 
                 tttcattcaa ctgttgcctc cggtt 
               
               
                   
               
               
                 754 
                 taacatttca ttcaactgtt gcctc 
               
               
                   
               
               
                 755 
                 ttgtgttgaa tcctttaaca tttca 
               
               
                   
               
               
                 756 
                 tcttccttag cttccagcca ttgtg 
               
               
                   
               
               
                 757 
                 cttagcttcc agccattgtg ttgaa 
               
               
                   
               
               
                 758 
                 gtcctaagac ctgctcagct tcttc 
               
               
                   
               
               
                 759 
                 ctgctcagct tcttccttag cttcc 
               
               
                   
               
               
                 760 
                 ctcaagcttg gctctggcct gtcct 
               
               
                   
               
               
                 761 
                 ggcctgtcct aagacctgct cagct 
               
               
                   
               
               
                 762 
                 tagggaccct ccttccatga ctcaa 
               
               
                   
               
               
                 763 
                 tttggattgc atctactgta taggg 
               
               
                   
               
               
                 764 
                 accctccttc catgactcaa gcttg 
               
               
                   
               
               
                 765 
                 cttggtttct gtgattttct tttgg 
               
               
                   
               
               
                 766 
                 atctactgta tagggaccct ccttc 
               
               
                   
               
               
                 767 
                 ctaaccttgg tttctgtgat tttct 
               
               
                   
               
               
                 768 
                 tttcttttgg attgcatcta ctgta 
               
               
                   
               
               
                 769 
                 tgatactaac cttggtttct gtgat 
               
               
                   
               
               
                 770 
                 atctttgata ctaaccttgg tttct 
               
               
                   
               
               
                 771 
                 aaggtatctt tgatactaac cttgg 
               
               
                   
               
               
                 772 
                 ttaaaaaggt atctttgata ctaac 
               
               
                   
               
               
                 773 
                 ataaaaggaa aaataaatat 
               
               
                   
               
               
                 774 
                 gaataaaagg aaaaataaat 
               
               
                   
               
               
                 775 
                 aactagaata aaaggaaaaa 
               
               
                   
               
               
                 776 
                 ctttcaacta gaataaaagg 
               
               
                   
               
               
                 777 
                 gaattctttc aactagaata 
               
               
                   
               
               
                 778 
                 attctgaatt ctttcaacta 
               
               
                   
               
               
                 779 
                 tacttcatcc cactgattct 
               
               
                   
               
               
                 780 
                 ctgaaggtgt tcttgtact 
               
               
                   
               
               
                 781 
                 ctgttgcctc cggttctgaa 
               
               
                   
               
               
                 782 
                 taacatttca ttcaactgtt 
               
               
                   
               
               
                 783 
                 ttgtgttgaa tcctttaaca 
               
               
                   
               
               
                 784 
                 cttagcttcc agccattgtg 
               
               
                   
               
               
                 785 
                 ctgctcagct tcttccttag 
               
               
                   
               
               
                 786 
                 ggcctgtcct aagacctgct 
               
               
                   
               
               
                 787 
                 ctcaagcttg gctctggcct 
               
               
                   
               
               
                 788 
                 accctccttc catgactcaa 
               
               
                   
               
               
                 789 
                 atctactgta tagggaccct 
               
               
                   
               
               
                 790 
                 tttcttttgg attgcatcta 
               
               
                   
               
               
                 791 
                 cttggtttct gtgattttct 
               
               
                   
               
               
                 792 
                 ctaaccttgg tttctgtgat 
               
               
                   
               
               
                 793 
                 tgatactaac cttggtttct 
               
               
                   
               
               
                 794 
                 atctttgata ctaaccttgg 
               
               
                   
               
               
                 795 
                 aaggtatctt tgatactaac 
               
               
                   
               
               
                 796 
                 ttaaaaaggt atctttgata 
               
               
                   
               
               
                 797 
                 ctatagattt ttatgagaaa gaga 
               
               
                   
               
               
                 798 
                 aactgctata gatttttatg agaaa 
               
               
                   
               
               
                 799 
                 tggccaactg ctatagattt ttatg 
               
               
                   
               
               
                 800 
                 gtctttggcc aactgctata gattt 
               
               
                   
               
               
                 801 
                 cggaggtctt tggccaactg ctata 
               
               
                   
               
               
                 802 
                 actggcggag gtctttggcc aactg 
               
               
                   
               
               
                 803 
                 tttgtctgcc actggcggag gtctt 
               
               
                   
               
               
                 804 
                 agtcatttgc cacatctaca tttgt 
               
               
                   
               
               
                 805 
                 tttgccacat ctacatttgt ctgcc 
               
               
                   
               
               
                 806 
                 ccggagaagt ttcagggcca agtca 
               
               
                   
               
               
                 807 
                 gtatcatctg cagaataatc ccgga 
               
               
                   
               
               
                 808 
                 taatcccgga gaagtttcag ggcca 
               
               
                   
               
               
                 809 
                 ttatcatgtg gacttttctg gtatc 
               
               
                   
               
               
                 810 
                 agaggcattg atattctctg ttatc 
               
               
                   
               
               
                 811 
                 atgtggactt ttctggtatc atctg 
               
               
                   
               
               
                 812 
                 cttttatgaa tgcttctcca agagg 
               
               
                   
               
               
                 813 
                 atattctctg ttatcatgtg gactt 
               
               
                   
               
               
                 814 
                 catacctttt atgaatgctt ctcca 
               
               
                   
               
               
                 815 
                 ctccaagagg cattgatatt ctctg 
               
               
                   
               
               
                 816 
                 taattcatac cttttatgaa tgctt 
               
               
                   
               
               
                 817 
                 taatgtaatt catacctttt atgaa 
               
               
                   
               
               
                 818 
                 agaaataatg taattcatac ctttt 
               
               
                   
               
               
                 819 
                 gttttagaaa taatgtaatt catac 
               
               
                   
               
               
                 820 
                 gatttttatg agaaagaga 
               
               
                   
               
               
                 821 
                 ctatagattt ttatgagaaa 
               
               
                   
               
               
                 822 
                 aactgctata gatttttatg 
               
               
                   
               
               
                 823 
                 tggccaactg ctatagattt 
               
               
                   
               
               
                 824 
                 gtctttggcc aactgctata 
               
               
                   
               
               
                 825 
                 cggaggtctt tggccaactg 
               
               
                   
               
               
                 826 
                 tttgtctgcc actggcggag 
               
               
                   
               
               
                 827 
                 tttgccacat ctacatttgt 
               
               
                   
               
               
                 828 
                 ttcagggcca agtcatttgc 
               
               
                   
               
               
                 829 
                 taatcccgga gaagtttcag 
               
               
                   
               
               
                 830 
                 gtatcatctg cagaataatc 
               
               
                   
               
               
                 831 
                 atgtggactt ttctggtatc 
               
               
                   
               
               
                 832 
                 atattctctg ttatcatgtg 
               
               
                   
               
               
                 833 
                 ctccaagagg cattgatatt 
               
               
                   
               
               
                 834 
                 cttttatgaa tgcttctcca 
               
               
                   
               
               
                 835 
                 catacctttt atgaatgctt 
               
               
                   
               
               
                 836 
                 taattcatac cttttatgaa 
               
               
                   
               
               
                 837 
                 taatgtaatt catacctttt 
               
               
                   
               
               
                 838 
                 agaaataatg taattcatac 
               
               
                   
               
               
                 839 
                 gttttagaaa taatgtaatt 
               
               
                   
               
               
                 840 
                 ctgcaaagga ccaaatgttc agatg 
               
               
                   
               
               
                 841 
                 tcaccctgca aaggaccaaa tgttc 
               
               
                   
               
               
                 842 
                 ctcactcacc ctgcaaagga ccaaa 
               
               
                   
               
               
                 843 
                 tctcgctcac tcaccctgca aagga 
               
               
                   
               
               
                 844 
                 cagcctctcg ctcactcacc ctgca 
               
               
                   
               
               
                 845 
                 caaagcagcc tctcgctcac tcacc 
               
               
                   
               
               
                 846 
                 tcttccaaag cagcctctcg ctcac 
               
               
                   
               
               
                 847 
                 tctatgagtt tcttccaaag cagcc 
               
               
                   
               
               
                 848 
                 gttgcagtaa tctatgagtt tcttc 
               
               
                   
               
               
                 849 
                 gaactgttgc agtaatctat gagtt 
               
               
                   
               
               
                 850 
                 ttccaggtcc agggggaact gttgc 
               
               
                   
               
               
                 851 
                 gtaagccagg caagaaactt ttcca 
               
               
                   
               
               
                 852 
                 ccaggcaaga aacttttcca ggtcc 
               
               
                   
               
               
                 853 
                 tggcagttgt ttcagcttct gtaag 
               
               
                   
               
               
                 854 
                 ttcagcttct gtaagccagg caaga 
               
               
                   
               
               
                 855 
                 ggtagcatcc tgtaggacat tggca 
               
               
                   
               
               
                 856 
                 gacattggca gttgtttcag cttct 
               
               
                   
               
               
                 857 
                 tctaggagcc tttccttacg ggtag 
               
               
                   
               
               
                 858 
                 cttttactcc cttggagtct tctag 
               
               
                   
               
               
                 859 
                 gagcctttcc ttacgggtag catcc 
               
               
                   
               
               
                 860 
                 ttgccattgt ttcatcagct ctttt 
               
               
                   
               
               
                 861 
                 cttggagtct tctaggagcc tttcc 
               
               
                   
               
               
                 862 
                 cttacttgcc attgtttcat cagct 
               
               
                   
               
               
                 863 
                 cagctctttt actcccttgg agtct 
               
               
                   
               
               
                 864 
                 cctgacttac ttgccattgt ttcat 
               
               
                   
               
               
                 865 
                 aaatgcctga cttacttgcc attgt 
               
               
                   
               
               
                 866 
                 agcggaaatg cctgacttac ttgcc 
               
               
                   
               
               
                 867 
                 gctaaagcgg aaatgcctga cttac 
               
               
                   
               
               
                 868 
                 aaggaccaaa tgttcagatg 
               
               
                   
               
               
                 869 
                 ctgcaaagga ccaaatgttc 
               
               
                   
               
               
                 870 
                 tcaccctgca aaggaccaaa 
               
               
                   
               
               
                 871 
                 ctcactcacc ctgcaaagga 
               
               
                   
               
               
                 872 
                 tctcgctcac tcaccctgca 
               
               
                   
               
               
                 873 
                 cagcctctcg ctcactcacc 
               
               
                   
               
               
                 874 
                 caaagcagcc tctcgctcac 
               
               
                   
               
               
                 875 
                 tctatgagtt tcttccaaag 
               
               
                   
               
               
                 876 
                 gaactgttgc agtaatctat 
               
               
                   
               
               
                 877 
                 ttccaggtcc agggggaact 
               
               
                   
               
               
                 878 
                 ccaggcaaga aacttttcca 
               
               
                   
               
               
                 879 
                 ttcagcttct gtaagccagg 
               
               
                   
               
               
                 880 
                 gacattggca gttgtttcag 
               
               
                   
               
               
                 881 
                 ggtagcatcc tgtaggacat 
               
               
                   
               
               
                 882 
                 gagcctttcc ttacgggtag 
               
               
                   
               
               
                 883 
                 cttggagtct tctaggagcc 
               
               
                   
               
               
                 884 
                 cagctctttt actcccttgg 
               
               
                   
               
               
                 885 
                 ttgccattgt ttcatcagct 
               
               
                   
               
               
                 886 
                 cttacttgcc attgtttcat 
               
               
                   
               
               
                 887 
                 cctgacttac ttgccattgt 
               
               
                   
               
               
                 888 
                 aaatgcctga cttacttgcc 
               
               
                   
               
               
                 889 
                 agcggaaatg cctgacttac 
               
               
                   
               
               
                 890 
                 gctaaagcgg aaatgcctga 
               
               
                   
               
               
                 891 
                 ccactcagag ctcagatctt ctaacttcc 
               
               
                   
               
               
                 892 
                 gggatccagt atacttacag gctcc 
               
               
                   
               
               
                 893 
                 cttccactca gagctcagat cttctaa 
               
               
                   
               
               
                 894 
                 acatcaagga agatggcatt tctagtttgg 
               
               
                   
               
               
                 895 
                 ctccaacatc aaggaagatg gcatttctag 
               
               
                   
               
               
                 896 
                 ttctgtccaa gcccggttga aatc 
               
               
                   
               
               
                 897 
                 cacccaccat caccctcygt g 
               
               
                   
               
               
                 898 
                 atcatctcgt tgatatcctc aa 
               
               
                   
               
               
                 899 
                 acatcaagga agatggcatt tctag 
               
               
                   
               
               
                 900 
                 accagagtaa cagtctgagt aggagc 
               
               
                   
               
               
                 901 
                 tcaaggaaga tggcatttct 
               
               
                   
               
               
                 902 
                 cctctgtgat tttataactt gat 
               
               
                   
               
               
                 903 
                 atcatttttt ctcatacctt ctgct 
               
               
                   
               
               
                 904 
                 ctcatacctt ctgcttgatg atc 
               
               
                   
               
               
                 905 
                 tggcatttct agtttgg 
               
               
                   
               
               
                 906 
                 ccagagcagg tacctccaac atc 
               
               
                   
               
               
                 907 
                 cgccgccatt tctcaacag 
               
               
                   
               
               
                 908 
                 tgtttttgag gattgctgaa 
               
               
                   
               
               
                 909 
                 gctgaattat ttcttcccc 
               
               
                   
               
               
                 910 
                 gcccaatgcc atcctgg 
               
               
                   
               
               
                 911 
                 ccaatgccat cctggagttc ctgtaa 
               
               
                   
               
               
                 912 
                 cattcaactg ttgcctccgg ttctgaaggt g 
               
               
                   
               
               
                 913 
                 ctgttgcctc cggttctg 
               
               
                   
               
               
                 914 
                 attctttcaa ctagaataaa ag 
               
               
                   
               
               
                 915 
                 gccatcctgg agttcctgta agataccaaa 
               
               
                   
               
               
                 916 
                 ccaatgccat cctggagttc ctgtaagata 
               
               
                   
               
               
                 917 
                 gccgctgccc aatgccatcc tggagttcct 
               
               
                   
               
               
                 918 
                 gtttgccgct gcccaatgcc atcctggagt 
               
               
                   
               
               
                 919 
                 caacagtttg ccgctgccca atgccatcct 
               
               
                   
               
               
                 920 
                 ctgacaacag tttgccgctg cccaatgcca 
               
               
                   
               
               
                 921 
                 tgttctgaca acagtttgcc gctgcccaat 
               
               
                   
               
               
                 922 
                 caatgttctg acaacagttt gccgctgccc 
               
               
                   
               
               
                 923 
                 cattcaatgt tctgacaaca gtttgccgct 
               
               
                   
               
               
                 924 
                 tatttcttcc ccagttgcat tcaatgttct 
               
               
                   
               
               
                 925 
                 gctgaattat ttcttcccca gttgcattca 
               
               
                   
               
               
                 926 
                 ggattgctga attatttctt ccccagttgc 
               
               
                   
               
               
                 927 
                 tttgaggatt gctgaattat ttcttcccca 
               
               
                   
               
               
                 928 
                 gtacttcatc ccactgattc tgaattcttt 
               
               
                   
               
               
                 929 
                 tcttgtactt catcccactg attctgaatt 
               
               
                   
               
               
                 930 
                 tgttcttgta cttcatccca ctgattctga 
               
               
                   
               
               
                 931 
                 cggttctgaa ggtgttcttg tacttcatcc 
               
               
                   
               
               
                 932 
                 ctccggttct gaaggtgttc ttgtacttca 
               
               
                   
               
               
                 933 
                 tgcctccggt tctgaaggtg ttcttgtact 
               
               
                   
               
               
                 934 
                 tgttgcctcc ggttctgaag gtgttcttgt 
               
               
                   
               
               
                 935 
                 aactgttgcc tccggttctg aaggtgttct 
               
               
                   
               
               
                 936 
                 ttcaactgtt gcctccggtt ctgaaggtgt 
               
               
                   
               
               
                 937 
                 ggccaaacct cggcttacct gaaat 
               
               
                   
               
               
                 938 
                 cagatctgtc aaatcgcctg cagg 
               
               
                   
               
               
                 939 
                 caacagatct gtcaaatcgc ctgcagg 
               
               
                   
               
               
                 940 
                 ctcaacagat ctgtcaaatc gcctgcagg 
               
               
                   
               
               
                 941 
                 gtgtctttct gagaaactgt tcagc 
               
               
                   
               
               
                 942 
                 gagaaactgt tcagcttctg ttagccac 
               
               
                   
               
               
                 943 
                 gaaactgttc agcttctgtt agccactg 
               
               
                   
               
               
                 944 
                 ctgttcagct tctgttagcc actg 
               
               
                   
               
               
                 945 
                 atctgtcaaa tcgcctgcag 
               
               
                   
               
               
                 946 
                 tttgtgtctt tctgagaaac 
               
               
                   
               
               
                 947 
                 tgttcagctt ctgttagcca ctga 
               
               
                   
               
               
                 948 
                 gatctgtcaa atcgcctgca ggtaa 
               
               
                   
               
               
                 949 
                 aaactgttca gcttctgtta gccac 
               
               
                   
               
               
                 950 
                 ttgtgtcttt ctgagaaact gttca 
               
               
                   
               
               
                 951 
                 caacagatct gtcaaatcgc ctgcag 
               
               
                   
               
               
                 952 
                 cagatctgtc aaatcgcctg caggta 
               
               
                   
               
               
                 953 
                 ctgttcagct tctgttagcc actgatt 
               
               
                   
               
               
                 954 
                 gaaactgttc agcttctgtt agccactgat t 
               
               
                   
               
               
                 955 
                 agaaactgtt cagcttctgt tagcca 
               
               
                   
               
               
                 956 
                 cttggacaga acttaccgac tgg 
               
               
                   
               
               
                 957 
                 gtttcttcca aagcagcctc tcg 
               
               
                   
               
               
                 958 
                 gcaggatttg gaacagaggc g 
               
               
                   
               
               
                 959 
                 catctacatt tgtctgccac tgg 
               
               
                   
               
               
                 960 
                 caatgctcct gacctctgtg c 
               
               
                   
               
               
                 961 
                 gctcttttcc aggttcaagt gg 
               
               
                   
               
               
                 962 
                 gtctacaaca aagctcaggt cg 
               
               
                   
               
               
                 963 
                 gcaatgttat ctgcttcctc caacc 
               
               
                   
               
               
                 964 
                 gctttgttgt agactatctt ttatattc 
               
               
                   
               
               
                 965 
                 ccgacctgag ctttgttgta gactatct 
               
               
                   
               
               
                 966 
                 cttcctgtag cttcaccctt tccacagg 
               
               
                   
               
               
                 967 
                 gctgggagag agcttcctgt agcttcac 
               
               
                   
               
               
                 968 
                 tgttacctac ccttgtcggt ccttgtac 
               
               
                   
               
               
                 969 
                 ctatgaataa tgtcaatccg acctgagc 
               
               
                   
               
               
                 970 
                 ctgctgtctt cttgctatga ataatgtc 
               
               
                   
               
               
                 971 
                 ggcgttgcac tttgcaatgc tgctgtct 
               
               
                   
               
               
                 972 
                 ttggaaatca agctgggaga gagcttcc 
               
               
                   
               
               
                 973 
                 ctttttccca ttggaaatca agctggga 
               
               
                   
               
               
                 974 
                 gtcggtcctt gtacattttg ttaacttt 
               
               
                   
               
               
                 975 
                 ctacccttgt cggtccttgt acattttg 
               
               
                   
               
               
                 976 
                 gacctgagct ttgttgtaga ctatcttt 
               
               
                   
               
               
                 977 
                 gtcaatccga cctgagcttt gttgtaga 
               
               
                   
               
               
                 978 
                 taatgtcaat ccgacctgag ctttgttg 
               
               
                   
               
               
                 979 
                 cttgctatga ataatgtcaa tccgacc 
               
               
                   
               
               
                 980 
                 gtcttcttgc tatgaataat gtcaatcc 
               
               
                   
               
               
                 981 
                 gcactttgca atgctgctgt cttcttgc 
               
               
                   
               
               
                 982 
                 ccacaggcgt tgcactttgc aatgctgc 
               
               
                   
               
               
                 983 
                 agcttcaccc tttccacagg cgttgcac 
               
               
                   
               
               
                 984 
                 tcaccctttc cacaggcgtt gca 
               
               
                   
               
               
                 985 
                 ggagagagct tcctgtagct 
               
               
                   
               
               
                 986 
                 tcccattgga aatcaagctg ggagagag 
               
               
                   
               
               
                 987 
                 tatatgtgtt acctaccctt gtcggtcc 
               
               
                   
               
               
                 988 
                 gccatcctgg agttcctgta agatacc 
               
               
                   
               
               
                 989 
                 gagttcctgt aagataccaa aaagg 
               
               
                   
               
               
                 990 
                 gcccaatgcc atcctggagt tcctg 
               
               
                   
               
               
                 991 
                 ccaatgccat cctggagttc ct 
               
               
                   
               
               
                 992 
                 aatgccatcc tggagttcct gtaa 
               
               
                   
               
               
                 993 
                 cctggagttc ctgtaagata ccaaa 
               
               
                   
               
               
                 994 
                 tgccatcctg gagttcctgt aagat 
               
               
                   
               
               
                 995 
                 tcctggagtt cctgtaagat ac 
               
               
                   
               
               
                 996 
                 ccatcctgga gttcctgtaa gatac 
               
               
                   
               
               
                 997 
                 cccaatgcca tcctggagtt cctgtaaga 
               
               
                   
               
               
                 998 
                 ccgctgccca atgccatcct ggagttcc 
               
               
                   
               
               
                 999 
                 caatgccatc ctggagttcc tgtaagatac 
               
               
                   
               
               
                 1000 
                 cccaatgcca tcctggagtt cctgtaagat 
               
               
                   
               
               
                 1001 
                 gccgctgccc aatgccatcc tggagttcct 
               
               
                   
               
               
                 1002 
                 aatgccatcc tggagttcct gtaagatacc 
               
               
                   
               
               
                 1003 
                 ccgctgccca atgccatcct ggagttcctg 
               
               
                   
               
               
                 1004 
                 tgccgctgcc caatgccatc ctggagttcc 
               
               
                   
               
               
                 1005 
                 tgcccaatgc catcctggag ttcctgtaag 
               
               
                   
               
               
                 1006 
                 caatgccatc ctggagttcc tgtaagat 
               
               
                   
               
               
                 1007 
                 cccaatgcca tcctggagtt cctgtaag 
               
               
                   
               
               
                 1008 
                 tgcccaatgc catcctggag ttcctgta 
               
               
                   
               
               
                 1009 
                 gctgcccaat gccatcctgg agttcctg 
               
               
                   
               
               
                 1010 
                 catcctggag ttcctgtaag atacc 
               
               
                   
               
               
                 1011 
                 gccatcctgg agttcctgta agatacc 
               
               
                   
               
               
                 1012 
                 gctgcccaat gccatcctgg agttc 
               
               
                   
               
               
                 1013 
                 gcccaatgcc atcctggagt 
               
               
                   
               
               
                 1014 
                 tgccgctgcc caatgccatc ctgga 
               
               
                   
               
               
                 1015 
                 ctgcccaatg ccatcctgg 
               
               
                   
               
               
                 1016 
                 cagtttgccg ctgcccaatg ccatcc 
               
               
                   
               
               
                 1017 
                 acagtttgcc gctgcccaat gcca 
               
               
                   
               
               
                 1018 
                 ctgacaacag tttgccgctg cccaa 
               
               
                   
               
               
                 1019 
                 gcattcaatg ttctgacaac 
               
               
                   
               
               
                 1020 
                 gaattatttc ttccccagtt gcattcaatg 
               
               
                   
               
               
                 1021 
                 ctggcatctg tttttgagga ttgctgaatt 
               
               
                   
               
               
                 1022 
                 ccagttgcat tcaatgttct gacaac 
               
               
                   
               
               
                 1023 
                 ttgctgaatt atttcttccc cag 
               
               
                   
               
               
                 1024 
                 tttttgagga ttgctgaatt atttcttcc 
               
               
                   
               
               
                 1025 
                 tttcctgtag aatactggca tctgt 
               
               
                   
               
               
                 1026 
                 cttcccaatt tttcctgtag aatactggca t 
               
               
                   
               
               
                 1027 
                 ccaatttttc ctgtagaata ctggc 
               
               
                   
               
               
                 1028 
                 caggcttccc aatttttcct gtagaatac 
               
               
                   
               
               
                 1029 
                 ctcctgccac cgcagattca ggcttc 
               
               
                   
               
               
                 1030 
                 gcagacctcc tgccaccgca gattc 
               
               
                   
               
               
                 1031 
                 ttgtttgcag acctcctgcc accgcagatt c 
               
               
                   
               
               
                 1032 
                 gctgtttgca gacctcctgc cacc 
               
               
                   
               
               
                 1033 
                 gtttgcagac ctcctgccac cgcag 
               
               
                   
               
               
                 1034 
                 cttttttctg tctgacagct gtttgcagac 
               
               
                   
               
               
                 1035 
                 ctgtctgaca gctgtttgca g 
               
               
                   
               
               
                 1036 
                 ctacctcttt tttctgtctg acagc 
               
               
                   
               
               
                 1037 
                 tattagatct gtcgccctac ctctt 
               
               
                   
               
               
                 1038 
                 cctattagat ctgtcgccct acctc 
               
               
                   
               
               
                 1039 
                 cuuuaacaga aaagcauac 
               
               
                   
               
               
                 1040 
                 ucuuuaacag aaaagcauac 
               
               
                   
               
               
                 1041 
                 ccucuuuaac agaaaagcau ac 
               
               
                   
               
               
                 1042 
                 aacuuccucu uuaacagaaa agcauac 
               
               
                   
               
               
                 1043 
                 cuucuaacuu ccucuuuaac agaaaagcau ac 
               
               
                   
               
               
                 1044 
                 ccucuuuaac agaaaa 
               
               
                   
               
               
                 1045 
                 aacuuccucu uuaacagaaa ag 
               
               
                   
               
               
                 1046 
                 aacuuccucu uuaacag 
               
               
                   
               
               
                 1047 
                 gcucagaucu ucuaacuucc ucuuuaacag 
               
               
                   
               
               
                 1048 
                 aacuuccucu uuaaca 
               
               
                   
               
               
                 1049 
                 ccacucagag cucagaucuu cuaacuucc 
               
               
                   
               
               
                 1050 
                 cucagagcuc agaucuu 
               
               
                   
               
               
                 1051 
                 gcucuugaag uaaacgg 
               
               
                   
               
               
                 1052 
                 aauagugguc aguccagg 
               
               
                   
               
               
                 1053 
                 cuuacaggcu ccaauagugg uca 
               
               
                   
               
               
                 1054 
                 guauacuuac aggcuccaau agugguca 
               
               
                   
               
               
                 1055 
                 uccaguauac uuacaggcuc caauaguggu 
               
               
                   
               
               
                 1056 
                 cuuacaggcu ccaauagu 
               
               
                   
               
               
                 1057 
                 guauacuuac aggcuccaau agu 
               
               
                   
               
               
                 1058 
                 uccaguauac uuacaggcuc caauagu 
               
               
                   
               
               
                 1059 
                 uccaguauac uuacaggcuc ca 
               
               
                   
               
               
                 1060 
                 gggauccagu auacuuacag gcucc 
               
               
                   
               
               
                 1061 
                 uccaguauac uuacaggcu 
               
               
                   
               
               
                 1062 
                 uccaguauac uuaca 
               
               
                   
               
               
                 1063 
                 ctccaacatc aaggaagatg gcatttct 
               
               
                   
               
               
                 1064 
                 catcaaggaa gatggcattt ctagt 
               
               
                   
               
               
                 1065 
                 ggagctaaaa tattttgggt ttttgc 
               
               
                   
               
               
                 1066 
                 ttttctcata ccttctgctt gatga 
               
               
                   
               
               
                 1067 
                 aggtacctcc aacatcaagg aagatgg 
               
               
                   
               
               
                 1068 
                 ctccaacatc aaggaagatg gcatt 
               
               
                   
               
               
                 1069 
                 ctccaacatc aaggaagatg gcatttct 
               
               
                   
               
               
                 1070 
                 ctccaacatc aaggaagatg gcatttctag 
               
               
                   
               
               
                 1071 
                 aaggaagatg gcatttctag tttgg 
               
               
                   
               
               
                 1072 
                 cagtctgagt aggagctaaa atatt 
               
               
                   
               
               
                 1073 
                 gagtaggagc taaaatattt tgggt 
               
               
                   
               
               
                 1074 
                 cugaauucuu ucaacuagaa uaaaa 
               
               
                   
               
               
                 1075 
                 gccauugugu ugaauccuuu aacauuuc 
               
               
                   
               
               
                 1076 
                 ccaugacuca agcuuggcuc uggcc 
               
               
                   
               
               
                 1077 
                 cccuauacag uagaugcaau 
               
               
                   
               
               
                 1078 
                 uugauacuaa ccuugguuuc ugug 
               
               
                   
               
               
                 1079 
                 caactgttgc ctccggttct gaag 
               
               
                   
               
               
                 1080 
                 ggaccctcct tccatgactc aagc 
               
               
                   
               
               
                 1081 
                 ggtatctttg atactaacct tggtttc 
               
               
                   
               
               
                 1082 
                 gcccaaugcc auccugg 
               
               
                   
               
               
                 1083 
                 cccauuuugu gaauguuuuc uuuu 
               
               
                   
               
               
                 1084 
                 uugugcauuu acccauuuug ug 
               
               
                   
               
               
                 1085 
                 uauccucuga augucgcauc 
               
               
                   
               
               
                 1086 
                 gguuauccuc ugaaugucgc 
               
               
                   
               
               
                 1087 
                 gagccuuuuu ucuucuuug 
               
               
                   
               
               
                 1088 
                 uccuuucguc ucugggcuc 
               
               
                   
               
               
                 1089 
                 cuccucuuuc uucuucugc 
               
               
                   
               
               
                 1090 
                 cuucgaaacu gagcaaauuu 
               
               
                   
               
               
                 1091 
                 cuugugagac augagug 
               
               
                   
               
               
                 1092 
                 cagagacucc ucuugcuu 
               
               
                   
               
               
                 1093 
                 ugcugcuguc uucuugcu 
               
               
                   
               
               
                 1094 
                 uuguuaacuu uuucccauu 
               
               
                   
               
               
                 1095 
                 cgccgccauu ucucaacag 
               
               
                   
               
               
                 1096 
                 uuuguauuua gcauguuccc 
               
               
                   
               
               
                 1097 
                 gcugaauuau uucuucccc 
               
               
                   
               
               
                 1098 
                 cugcuuccuc caacc 
               
               
                   
               
               
                 1099 
                 gcuuuucuuu uaguugcugc 
               
               
                   
               
               
                 1100 
                 ucuugcucuu cugggcuu 
               
               
                   
               
               
                 1101 
                 cuugagcuua uuuucaaguu u 
               
               
                   
               
               
                 1102 
                 uuucuccuug uuucuc 
               
               
                   
               
               
                 1103 
                 ccauaaauuu ccaacugauu c 
               
               
                   
               
               
                 1104 
                 cuuccacauc cgguuguuu 
               
               
                   
               
               
                 1105 
                 guggcugguu uuuccuugu 
               
               
                   
               
               
                 1106 
                 cucagagcuc agaucuu 
               
               
                   
               
               
                 1107 
                 ggcugcuuug cccuc 
               
               
                   
               
               
                 1108 
                 ucaaggaaga uggcauuucu 
               
               
                   
               
               
                 1109 
                 ccucugugau uuuauaacuu gau 
               
               
                   
               
               
                 1110 
                 cuguugccuc cgguucug 
               
               
                   
               
               
                 1111 
                 uuggcucugg ccuguccu 
               
               
                   
               
               
                 1112 
                 gaaaauugug cauuuaccca uuuu 
               
               
                   
               
               
                 1113 
                 cuuccuggau ggcuucaau 
               
               
                   
               
               
                 1114 
                 guacauuaag auggacuuc 
               
               
                   
               
               
                 1115 
                 ccauuacagu ugucuguguu 
               
               
                   
               
               
                 1116 
                 uaaucugccu cuucuuuugg 
               
               
                   
               
               
                 1117 
                 ucugcuggca ucuugc 
               
               
                   
               
               
                 1118 
                 ccaucuguua gggucugug 
               
               
                   
               
               
                 1119 
                 ucugugccaa uaugcgaauc 
               
               
                   
               
               
                 1120 
                 uuaaaugucu caaguucc 
               
               
                   
               
               
                 1121 
                 guaguucccu ccaacg 
               
               
                   
               
               
                 1122 
                 cauguaguuc ccucc 
               
               
                   
               
               
                 1123 
                 uguuaacuuu uucccauugg 
               
               
                   
               
               
                 1124 
                 cauuuuguua acuuuuuccc 
               
               
                   
               
               
                 1125 
                 ucuguuuuug aggauugc 
               
               
                   
               
               
                 1126 
                 ccaccgcaga uucaggc 
               
               
                   
               
               
                 1127 
                 uuugcagacc uccugcc 
               
               
                   
               
               
                 1128 
                 gaaauucuga caagauauuc u 
               
               
                   
               
               
                 1129 
                 uaaaacaaau ucauu 
               
               
                   
               
               
                 1130 
                 uccagguuca agugggauac 
               
               
                   
               
               
                 1131 
                 uuccagguuc aagug 
               
               
                   
               
               
                 1132 
                 ucaagcuuuu cuuuuag 
               
               
                   
               
               
                 1133 
                 cugacaagau auucuu 
               
               
                   
               
               
                 1134 
                 agguucaagu gggauacua 
               
               
                   
               
               
                 1135 
                 uccaguuuca uuuaauuguu ug 
               
               
                   
               
               
                 1136 
                 cugcuugagc uuauuuucaa guu 
               
               
                   
               
               
                 1137 
                 agcacuuaca agcacgggu 
               
               
                   
               
               
                 1138 
                 uucaaguuua ucuugcucuu c 
               
               
                   
               
               
                 1139 
                 ggucuuuuau uugagcuuc 
               
               
                   
               
               
                 1140 
                 cuucaagcuu uuuuucaagc u 
               
               
                   
               
               
                 1141 
                 gcuucaauuu cuccuuguu 
               
               
                   
               
               
                 1142 
                 uuuauuugag cuucaauuu 
               
               
                   
               
               
                 1143 
                 gcugcccaag gucuuuu 
               
               
                   
               
               
                 1144 
                 cuucaagguc uucaagcuuu u 
               
               
                   
               
               
                 1145 
                 uaacugcucu ucaaggucuu c 
               
               
                   
               
               
                 1146 
                 gaaagccagu cgguaaguuc 
               
               
                   
               
               
                 1147 
                 cacccaccau caccc 
               
               
                   
               
               
                 1148 
                 ugauauccuc aaggucaccc 
               
               
                   
               
               
                 1149 
                 uugcuggucu uguuuuuc 
               
               
                   
               
               
                 1150 
                 ccguaaugau uguucu 
               
               
                   
               
               
                 1151 
                 uacauuuguc ugccacugg 
               
               
                   
               
               
                 1152 
                 cccggagaag uuucaggg 
               
               
                   
               
               
                 1153 
                 cuguugcagu aaucuaugag 
               
               
                   
               
               
                 1154 
                 ugccauuguu ucaucagcuc uuu 
               
               
                   
               
               
                 1155 
                 ugcaguaauc uaugaguuuc 
               
               
                   
               
               
                 1156 
                 uccuguagga cauuggcagu 
               
               
                   
               
               
                 1157 
                 gagucuucua ggagccuu 
               
               
                   
               
               
                 1158 
                 uuuuuuggcu guuuucaucc 
               
               
                   
               
               
                 1159 
                 guucacucca cuugaaguuc 
               
               
                   
               
               
                 1160 
                 ccuuccaggg aucucagg 
               
               
                   
               
               
                 1161 
                 uaggugccug ccggcuu 
               
               
                   
               
               
                 1162 
                 cugaacugcu ggaaagucgc c 
               
               
                   
               
               
                 1163 
                 uucagcugua gccacacc 
               
               
                   
               
               
                 1164 
                 uucuuuaguu uucaauuccc uc 
               
               
                   
               
               
                 1165 
                 gaguuucucu aguccuucc 
               
               
                   
               
               
                 1166 
                 caauuuuucc cacucaguau u 
               
               
                   
               
               
                 1167 
                 uugaaguucc uggagucuu 
               
               
                   
               
               
                 1168 
                 guucucuuuc agaggcgc 
               
               
                   
               
               
                 1169 
                 gugcugaggu uauacggug 
               
               
                   
               
               
                 1170 
                 gucccugugg gcuucaug 
               
               
                   
               
               
                 1171 
                 gugcugagau gcuggacc 
               
               
                   
               
               
                 1172 
                 uggcucucuc ccaggg 
               
               
                   
               
               
                 1173 
                 gggcacuuug uuuggcg 
               
               
                   
               
               
                 1174 
                 ggucccagca aguuguuug 
               
               
                   
               
               
                 1175 
                 guagagcucu gucauuuugg g 
               
               
                   
               
               
                 1176 
                 gccagaaguu gaucagagu 
               
               
                   
               
               
                 1177 
                 ucuacuggcc agaaguug 
               
               
                   
               
               
                 1178 
                 ugaguaucau cgugugaaag 
               
               
                   
               
               
                 1179 
                 gcauaauguu caaugcgug 
               
               
                   
               
               
                 1180 
                 gauccauugc uguuuucc 
               
               
                   
               
               
                 1181 
                 gagaugcuau cauuuagaua a 
               
               
                   
               
               
                 1182 
                 cuggcucagg ggggagu 
               
               
                   
               
               
                 1183 
                 uccccucuuu ccucacucu 
               
               
                   
               
               
                 1184 
                 ccuuuauguu cgugcugcu 
               
               
                   
               
               
                 1185 
                 ggcggccuuu guguugac 
               
               
                   
               
               
                 1186 
                 gagagguaga aggagagga 
               
               
                   
               
               
                 1187 
                 auaggcugac ugcugucgg 
               
               
                   
               
               
                 1188 
                 uuguguccug gggagga 
               
               
                   
               
               
                 1189 
                 ugcuccauca ccuccucu 
               
               
                   
               
               
                 1190 
                 gcuuuccagg gguauuuc 
               
               
                   
               
               
                 1191 
                 cauuggcuuu ccagggg 
               
               
                   
               
               
                 1192 
                 cccauuuugu gaauguuuuc uuuu 
               
               
                   
               
               
                 1193 
                 uugugcauuu acccauuuug ug 
               
               
                   
               
               
                 1194 
                 gaaaauugug cauuuaccca uuuu 
               
               
                   
               
               
                 1195 
                 cuuccuggau ggcuucaau 
               
               
                   
               
               
                 1196 
                 guacauuaag auggacuuc 
               
               
                   
               
               
                 1197 
                 ccauuacagu ugucuguguu 
               
               
                   
               
               
                 1198 
                 uaaucugccu cuucuuuugg 
               
               
                   
               
               
                 1199 
                 ucugcuggca ucuugc 
               
               
                   
               
               
                 1200 
                 uauccucuga augucgcauc 
               
               
                   
               
               
                 1201 
                 gguuauccuc ugaaugucgc 
               
               
                   
               
               
                 1202 
                 ccaucuguua gggucugug 
               
               
                   
               
               
                 1203 
                 ucugugccaa uaugcgaauc 
               
               
                   
               
               
                 1204 
                 uuaaaugucu caaguucc 
               
               
                   
               
               
                 1205 
                 guaguucccu ccaacg 
               
               
                   
               
               
                 1206 
                 cauguaguuc ccucc 
               
               
                   
               
               
                 1207 
                 gagccuuuuu ucuucuuug 
               
               
                   
               
               
                 1208 
                 uccuuucauc ucugggcuc 
               
               
                   
               
               
                 1209 
                 cuccucuuuc uucuucugc 
               
               
                   
               
               
                 1210 
                 cuucgaaacu gagcaaauuu 
               
               
                   
               
               
                 1211 
                 cuugugagac augagug 
               
               
                   
               
               
                 1212 
                 cagagacucc ucuugcuu 
               
               
                   
               
               
                 1213 
                 ugcugcuguc uucuugcu 
               
               
                   
               
               
                 1214 
                 uuguuaacuu uuucccauu 
               
               
                   
               
               
                 1215 
                 uguuaacuuu uucccauugg 
               
               
                   
               
               
                 1216 
                 cauuuuguua acuuuuuccc 
               
               
                   
               
               
                 1217 
                 cuguagcuuc acccuuucc 
               
               
                   
               
               
                 1218 
                 cgccgccauu ucucaacag 
               
               
                   
               
               
                 1219 
                 uuuguauuua gcauguuccc 
               
               
                   
               
               
                 1220 
                 gcugaauuau uucuucccc 
               
               
                   
               
               
                 1221 
                 uuuuucuguc ugacagcug 
               
               
                   
               
               
                 1222 
                 ucuguuuuug aggauugc 
               
               
                   
               
               
                 1223 
                 ccaccgcaga uucaggc 
               
               
                   
               
               
                 1224 
                 gcccaaugcc auccugg 
               
               
                   
               
               
                 1225 
                 uuugcagacc uccugcc 
               
               
                   
               
               
                 1226 
                 cugcuuccuc caacc 
               
               
                   
               
               
                 1227 
                 guuaucugcu uccuccaacc 
               
               
                   
               
               
                 1228 
                 gcuuuucuuu uaguugcugc 
               
               
                   
               
               
                 1229 
                 uuaguugcug cucuu 
               
               
                   
               
               
                 1230 
                 gaaauucuga caagauauuc u 
               
               
                   
               
               
                 1231 
                 uaaaacaaau ucauu 
               
               
                   
               
               
                 1232 
                 uccagguuca agugggauac 
               
               
                   
               
               
                 1233 
                 uuccagguuc aagug 
               
               
                   
               
               
                 1234 
                 ucaagcuuuu cuuuuag 
               
               
                   
               
               
                 1235 
                 cugacaagau auucuu 
               
               
                   
               
               
                 1236 
                 agguucaagu gggauacua 
               
               
                   
               
               
                 1237 
                 ucuugcucuu cugggcuu 
               
               
                   
               
               
                 1238 
                 cuugagcuua uuuucaaguu u 
               
               
                   
               
               
                 1239 
                 uccaguuuca uuuaauuguu ug 
               
               
                   
               
               
                 1240 
                 cugcuugagc uuauuuucaa guu 
               
               
                   
               
               
                 1241 
                 agcacuuaca agcacgggu 
               
               
                   
               
               
                 1242 
                 uucaaguuua ucuugcucuu c 
               
               
                   
               
               
                 1243 
                 uuucuccuug uuucuc 
               
               
                   
               
               
                 1244 
                 uuauaaauuu ccaacugauu c 
               
               
                   
               
               
                 1245 
                 ggucuuuuau uugagcuuc 
               
               
                   
               
               
                 1246 
                 cuucaagcuu uuuuucaagc u 
               
               
                   
               
               
                 1247 
                 gcuucaauuu cuccuuguu 
               
               
                   
               
               
                 1248 
                 uuuauuugag cuucaauuu 
               
               
                   
               
               
                 1249 
                 gcugcccaag gucuuuu 
               
               
                   
               
               
                 1250 
                 cuucaagguc uucaagcuuu u 
               
               
                   
               
               
                 1251 
                 uaacugcucu ucaaggucuu c 
               
               
                   
               
               
                 1252 
                 cuuccacauc cgguuguuu 
               
               
                   
               
               
                 1253 
                 guggcugguu uuuccuugu 
               
               
                   
               
               
                 1254 
                 cucagagcuc agaucuu 
               
               
                   
               
               
                 1255 
                 ggcugcuuug cccuc 
               
               
                   
               
               
                 1256 
                 ucaaggaaga uggcauuucu 
               
               
                   
               
               
                 1257 
                 gaaagccagu cgguaaguuc 
               
               
                   
               
               
                 1258 
                 cacccaccau caccc 
               
               
                   
               
               
                 1259 
                 ccucugugau uuuauaacuu gau 
               
               
                   
               
               
                 1260 
                 ugauauccuc aaggucaccc 
               
               
                   
               
               
                 1261 
                 uugcuggucu uguuuuuc 
               
               
                   
               
               
                 1262 
                 ccguaaugau uguucu 
               
               
                   
               
               
                 1263 
                 cuguugccuc cgguucug 
               
               
                   
               
               
                 1264 
                 uuggcucugg ccuguccu 
               
               
                   
               
               
                 1265 
                 uacauuuguc ugccacugg 
               
               
                   
               
               
                 1266 
                 cccggagaag uuucaggg 
               
               
                   
               
               
                 1267 
                 cuguugcagu aaucuaugag 
               
               
                   
               
               
                 1268 
                 ugccauuguu ucaucagcuc uuu 
               
               
                   
               
               
                 1269 
                 ugcaguaauc uaugaguuuc 
               
               
                   
               
               
                 1270 
                 uccuguagga cauuggcagu 
               
               
                   
               
               
                 1271 
                 gagucuucua ggagccuu 
               
               
                   
               
               
                 1272 
                 uuuuuuggcu guuuucaucc 
               
               
                   
               
               
                 1273 
                 guucacucca cuugaaguuc 
               
               
                   
               
               
                 1274 
                 ccuuccaggg aucucagg 
               
               
                   
               
               
                 1275 
                 uaggugccug ccggcuu 
               
               
                   
               
               
                 1276 
                 cugaacugcu ggaaagucgc c 
               
               
                   
               
               
                 1277 
                 uucagcugua gccacacc 
               
               
                   
               
               
                 1278 
                 uucuuuaguu uucaauuccc uc 
               
               
                   
               
               
                 1279 
                 gaguuucucu aguccuucc 
               
               
                   
               
               
                 1280 
                 caauuuuucc cacucaguau u 
               
               
                   
               
               
                 1281 
                 uugaaguucc uggagucuu 
               
               
                   
               
               
                 1282 
                 guucucuuuc agaggcgc 
               
               
                   
               
               
                 1283 
                 gugcugaggu uauacggug 
               
               
                   
               
               
                 1284 
                 gucccugugg gcuucaug 
               
               
                   
               
               
                 1285 
                 gugcugagau gcuggacc 
               
               
                   
               
               
                 1286 
                 uggcucucuc ccaggg 
               
               
                   
               
               
                 1287 
                 gggcacuuug uuuggcg 
               
               
                   
               
               
                 1288 
                 ggucccagca aguuguuug 
               
               
                   
               
               
                 1289 
                 guagagcucu gucauuuugg g 
               
               
                   
               
               
                 1290 
                 gccagaaguu gaucagagu 
               
               
                   
               
               
                 1291 
                 ucuacuggcc agaaguug 
               
               
                   
               
               
                 1292 
                 ugaguaucau cgugugaaag 
               
               
                   
               
               
                 1293 
                 gcauaauguu caaugcgug 
               
               
                   
               
               
                 1294 
                 gauccauugc uguuuucc 
               
               
                   
               
               
                 1295 
                 gagaugcuau cauuuagaua a 
               
               
                   
               
               
                 1296 
                 cuggcucagg ggggagu 
               
               
                   
               
               
                 1297 
                 uccccucuuu ccucacucu 
               
               
                   
               
               
                 1298 
                 ccuuuauguu cgugcugcu 
               
               
                   
               
               
                 1299 
                 ggcggccuuu guguugac 
               
               
                   
               
               
                 1300 
                 gagagguaga aggagagga 
               
               
                   
               
               
                 1301 
                 auaggcugac ugcugucgg 
               
               
                   
               
               
                 1302 
                 uuguguccug gggagga 
               
               
                   
               
               
                 1303 
                 ugcuccauca ccuccucu 
               
               
                   
               
               
                 1304 
                 gcuuuccagg gguauuuc 
               
               
                   
               
               
                 1305 
                 cauuggcuuu ccagggg 
               
               
                   
               
               
                 1306 
                 cugacgucca gucuuuauc 
               
               
                   
               
               
                 1307 
                 gggauuuucc gucugcuu 
               
               
                   
               
               
                 1308 
                 ccgccauuuc ucaacag 
               
               
                   
               
               
                 1309 
                 uucucaggaa uuugugucuu u 
               
               
                   
               
               
                 1310 
                 caguuugccg cugccca 
               
               
                   
               
               
                 1311 
                 guugcauuca auguucugac 
               
               
                   
               
               
                 1312 
                 auuuuuccug uagaauacug g 
               
               
                   
               
               
                 1313 
                 gcuggucuug uuuuucaa 
               
               
                   
               
               
                 1314 
                 uggucuuguu uuucaaauuu 
               
               
                   
               
               
                 1315 
                 gucuuguuuu ucaaauuuug 
               
               
                   
               
               
                 1316 
                 cuuguuuuuc aaauuuuggg 
               
               
                   
               
               
                 1317 
                 uguuuuucaa auuuugggc 
               
               
                   
               
               
                 1318 
                 uccuauaagc ugagaaucug 
               
               
                   
               
               
                 1319 
                 gccuucugca gucuucgg 
               
               
                   
               
               
                 1320 
                 ccggttctga aggtgttctt gta 
               
               
                   
               
               
                 1321 
                 tccggttctg aaggtgttct tgta 
               
               
                   
               
               
                 1322 
                 ctccggttct gaaggtgttc ttgta 
               
               
                   
               
               
                 1323 
                 cctccggttc tgaaggtgtt cttgta 
               
               
                   
               
               
                 1324 
                 gcctccggtt ctgaaggtgt tcttgta 
               
               
                   
               
               
                 1325 
                 tgcctccggt tctgaaggtg ttcttgta 
               
               
                   
               
               
                 1326 
                 ccggttctga aggtgttctt gt 
               
               
                   
               
               
                 1327 
                 tccggttctg aaggtgttct tgt 
               
               
                   
               
               
                 1328 
                 ctccggttct gaaggtgttc ttgt 
               
               
                   
               
               
                 1329 
                 cctccggttc tgaaggtgtt cttgt 
               
               
                   
               
               
                 1330 
                 gcctccggtt ctgaaggtgt tcttgt 
               
               
                   
               
               
                 1331 
                 tgcctccggt tctgaaggtg ttcttgt 
               
               
                   
               
               
                 1332 
                 ccggttctga aggtgttctt g 
               
               
                   
               
               
                 1333 
                 tccggttctg aaggtgttct tg 
               
               
                   
               
               
                 1334 
                 ctccggttct gaaggtgttc ttg 
               
               
                   
               
               
                 1335 
                 cctccggttc tgaaggtgtt cttg 
               
               
                   
               
               
                 1336 
                 gcctccggtt ctgaaggtgt tcttg 
               
               
                   
               
               
                 1337 
                 tgcctccggt tctgaaggtg ttcttg 
               
               
                   
               
               
                 1338 
                 ccggttctga aggtgttctt 
               
               
                   
               
               
                 1339 
                 tccggttctg aaggtgttct t 
               
               
                   
               
               
                 1340 
                 ctccggttct gaaggtgttc tt 
               
               
                   
               
               
                 1341 
                 cctccggttc tgaaggtgtt ctt 
               
               
                   
               
               
                 1342 
                 gcctccggtt ctgaaggtgt tctt 
               
               
                   
               
               
                 1343 
                 tgcctccggt tctgaaggtg ttctt 
               
               
                   
               
               
                 1344 
                 ccggttctga aggtgttct 
               
               
                   
               
               
                 1345 
                 tccggttctg aaggtgttct 
               
               
                   
               
               
                 1346 
                 ctccggttct gaaggtgttc t 
               
               
                   
               
               
                 1347 
                 cctccggttc tgaaggtgtt ct 
               
               
                   
               
               
                 1348 
                 gcctccggtt ctgaaggtgt tct 
               
               
                   
               
               
                 1349 
                 tgcctccggt tctgaaggtg ttct 
               
               
                   
               
               
                 1350 
                 ccggttctga aggtgttc 
               
               
                   
               
               
                 1351 
                 tccggttctg aaggtgttc 
               
               
                   
               
               
                 1352 
                 ctccggttct gaaggtgttc 
               
               
                   
               
               
                 1353 
                 cctccggttc tgaaggtgtt c 
               
               
                   
               
               
                 1354 
                 gcctccggtt ctgaaggtgt tc 
               
               
                   
               
               
                 1355 
                 tgcctccggt tctgaaggtg ttc 
               
               
                   
               
               
                 1356 
                 cattcaactg ttgcctccgg ttctgaaggt g 
               
               
                   
               
               
                 1357 
                 ttgcctccgg ttctgaaggt gttcttgtac 
               
               
                   
               
               
                 1358 
                 aggatttgga acagaggcgt c 
               
               
                   
               
               
                 1359 
                 gtctgccact ggcggaggtc 
               
               
                   
               
               
                 1360 
                 catcaagcag aaggcaacaa 
               
               
                   
               
               
                 1361 
                 gaagtttcag ggccaagtca 
               
               
                   
               
               
                 1362 
                 cgggcttgga cagaacttac 
               
               
                   
               
               
                 1363 
                 tccttacggg tagcatcctg 
               
               
                   
               
               
                 1364 
                 ctgaaggtgt tcttgtactt catcc 
               
               
                   
               
               
                 1365 
                 tgttgagaaa tggcggcgt 
               
               
                   
               
               
                 1366 
                 cauucaacug uugccuccgg uucugaaggu g 
               
               
                   
               
               
                 1367 
                 ucccacugau ucugaauucu uucaa 
               
               
                   
               
               
                 1368 
                 cuucauccca cugauucuga auucu 
               
               
                   
               
               
                 1369 
                 uuguacuuca ucccacugau ucuga 
               
               
                   
               
               
                 1370 
                 uguucuugua cuucauccca cugau 
               
               
                   
               
               
                 1371 
                 gaagguguuc uuguacuuca uccca 
               
               
                   
               
               
                 1372 
                 guucugaagg uguucuugua cuuca 
               
               
                   
               
               
                 1373 
                 cuccgguucu gaagguguuc uugua 
               
               
                   
               
               
                 1374 
                 guugccuccg guucugaagg uguuc 
               
               
                   
               
               
                 1375 
                 caacuguugc cuccgguucu gaagg 
               
               
                   
               
               
                 1376 
                 ucauucaacu guugccuccg guucu 
               
               
                   
               
               
                 1377 
                 acauuucauu caacuguugc cuccg 
               
               
                   
               
               
                 1378 
                 cuuuaacauu ucauucaacu guugc 
               
               
                   
               
               
                 1379 
                 gaauccuuua acauuucauu caacu 
               
               
                   
               
               
                 1380 
                 guguugaauc cuuuaacauu ucauu 
               
               
                   
               
               
                 1381 
                 ccauuguguu gaauccuuua acauu 
               
               
                   
               
               
                 1382 
                 uccagccauu guguugaauc cuuua 
               
               
                   
               
               
                 1383 
                 uagcuuccag ccauuguguu gaauc 
               
               
                   
               
               
                 1384 
                 uuccuuagcu uccagccauu guguu 
               
               
                   
               
               
                 1385 
                 gcuucuuccu uagcuuccag ccauu 
               
               
                   
               
               
                 1386 
                 gcucagcuuc uuccuuagcu uccag 
               
               
                   
               
               
                 1387 
                 gaccugcuca gcuucuuccu uagcu 
               
               
                   
               
               
                 1388 
                 ccuaagaccu gcucagcuuc uuccu 
               
               
                   
               
               
                 1389 
                 ccuguccuaa gaccugcuca gcuuc 
               
               
                   
               
               
                 1390 
                 ucuggccugu ccuaagaccu gcuca 
               
               
                   
               
               
                 1391 
                 uuggcucugg ccuguccuaa gaccu 
               
               
                   
               
               
                 1392 
                 caagcuuggc ucuggccugu ccuaa 
               
               
                   
               
               
                 1393 
                 ugacucaagc uuggcucugg ccugu 
               
               
                   
               
               
                 1394 
                 uuccaugacu caagcuuggc ucugg 
               
               
                   
               
               
                 1395 
                 ccuccuucca ugacucaagc uuggc 
               
               
                   
               
               
                 1396 
                 gggacccucc uuccaugacu caagc 
               
               
                   
               
               
                 1397 
                 guauagggac ccuccuucca ugacu 
               
               
                   
               
               
                 1398 
                 cuacuguaua gggacccucc uucca 
               
               
                   
               
               
                 1399 
                 ugcaucuacu guauagggac ccucc 
               
               
                   
               
               
                 1400 
                 uggauugcau cuacuguaua gggac 
               
               
                   
               
               
                 1401 
                 ucuuuuggau ugcaucuacu guaua 
               
               
                   
               
               
                 1402 
                 gauuuucuuu uggauugcau cuacu 
               
               
                   
               
               
                 1403 
                 ucugugauuu ucuuuuggau ugcau 
               
               
                   
               
               
                 1404 
                 ugguuucugu gauuuucuuu uggau 
               
               
                   
               
               
                 1405 
                 ccuuagcuuc cagccauugu guuga 
               
               
                   
               
               
                 1406 
                 ucuuccuuag cuuccagcca uugug 
               
               
                   
               
               
                 1407 
                 ggcucuggcc uguccuaaga ccugc 
               
               
                   
               
               
                 1408 
                 agcuuggcuc uggccugucc uaaga 
               
               
                   
               
               
                 1409 
                 cucaagcuug gcucuggccu guccu 
               
               
                   
               
               
                 1410 
                 gacccuccuu ccaugacuca agcuu 
               
               
                   
               
               
                 1411 
                 auagggaccc uccuuccaug acuca 
               
               
                   
               
               
                 1412 
                 cuguauaggg acccuccuuc cauga 
               
               
                   
               
               
                 1413 
                 ugugauuuuc uuuuggauug caucu 
               
               
                   
               
               
                 1414 
                 guuucuguga uuuucuuuug gauug 
               
               
                   
               
               
                 1415 
                 cuugguuucu gugauuuucu uuugg 
               
               
                   
               
               
                 1416 
                 ccgguucuga agguguucuu guacu 
               
               
                   
               
               
                 1417 
                 uccgguucug aagguguucu uguac 
               
               
                   
               
               
                 1418 
                 ccuccgguuc ugaagguguu cuugu 
               
               
                   
               
               
                 1419 
                 gccuccgguu cugaaggugu ucuug 
               
               
                   
               
               
                 1420 
                 ugccuccggu ucugaaggug uucuu 
               
               
                   
               
               
                 1421 
                 uugccuccgg uucugaaggu guucu 
               
               
                   
               
               
                 1422 
                 uguugccucc gguucugaag guguu 
               
               
                   
               
               
                 1423 
                 cuguugccuc cgguucugaa ggugu 
               
               
                   
               
               
                 1424 
                 acuguugccu ccgguucuga aggug 
               
               
                   
               
               
                 1425 
                 aacuguugcc uccgguucug aaggu 
               
               
                   
               
               
                 1426 
                 uguugccucc gguucugaag guguucuugu 
               
               
                   
               
               
                 1427 
                 gguucugaag guguucuugu 
               
               
                   
               
               
                 1428 
                 uccgguucug aagguguucu 
               
               
                   
               
               
                 1429 
                 ccuccgguuc ugaagguguu 
               
               
                   
               
               
                 1430 
                 uugccuccgg uucugaaggu 
               
               
                   
               
               
                 1431 
                 uguugccucc gguucugaag 
               
               
                   
               
               
                 1432 
                 uucugaaggu guucuugu 
               
               
                   
               
               
                 1433 
                 cgguucugaa gguguucu 
               
               
                   
               
               
                 1434 
                 cuccgguucu gaaggugu 
               
               
                   
               
               
                 1435 
                 ugccuccggu ucugaagg 
               
               
                   
               
               
                 1436 
                 uguugccucc gguucuga 
               
               
                   
               
               
                 1437 
                 uucugaaggu guucu 
               
               
                   
               
               
                 1438 
                 uccgguucug aaggu 
               
               
                   
               
               
                 1439 
                 uugccuccgg uucug 
               
               
                   
               
               
                 1440 
                 cuguugccuc cgguucug 
               
               
                   
               
               
                 1441 
                 caatgccatc ctggagttcc t 
               
               
                   
               
               
                 1442 
                 ccaatgccat cctggagttc c 
               
               
                   
               
               
                 1443 
                 cccaatgcca tcctggagtt c 
               
               
                   
               
               
                 1444 
                 gcccaatgcc atcctggagt t 
               
               
                   
               
               
                 1445 
                 tgcccaatgc catcctggag t 
               
               
                   
               
               
                 1446 
                 cccaatgcca tcctggagtt cctgt 
               
               
                   
               
               
                 1447 
                 cagtttgccg ctgcccaatg ccatcctgga 
               
               
                   
               
               
                 1448 
                 ccaatgccat cctggagttc 
               
               
                   
               
               
                 1449 
                 cccaatgcca tcctggagtt 
               
               
                   
               
               
                 1450 
                 cccaatgcca tcctggagtt c 
               
               
                   
               
               
                 1451 
                 gcugcccaau gccauccugg aguuc 
               
               
                   
               
               
                 1452 
                 uugccgcugc ccaaugccau ccugg 
               
               
                   
               
               
                 1453 
                 acaguuugcc gcugcccaau gccau 
               
               
                   
               
               
                 1454 
                 ugacaacagu uugccgcugc ccaau 
               
               
                   
               
               
                 1455 
                 uguucugaca acaguuugcc gcugc 
               
               
                   
               
               
                 1456 
                 uucaauguuc ugacaacagu uugcc 
               
               
                   
               
               
                 1457 
                 uugcauucaa uguucugaca acagu 
               
               
                   
               
               
                 1458 
                 cccaguugca uucaauguuc ugaca 
               
               
                   
               
               
                 1459 
                 ucuuccccag uugcauucaa uguuc 
               
               
                   
               
               
                 1460 
                 uuauuucuuc cccaguugca uucaa 
               
               
                   
               
               
                 1461 
                 cugaauuauu ucuuccccag uugca 
               
               
                   
               
               
                 1462 
                 gauugcugaa uuauuucuuc cccag 
               
               
                   
               
               
                 1463 
                 uugaggauug cugaauuauu ucuuc 
               
               
                   
               
               
                 1464 
                 uguuuuugag gauugcugaa uuauu 
               
               
                   
               
               
                 1465 
                 gcaucuguuu uugaggauug cugaa 
               
               
                   
               
               
                 1466 
                 uacuggcauc uguuuuugag gauug 
               
               
                   
               
               
                 1467 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 1468 
                 gctcaggtcg gattgacatt 
               
               
                   
               
               
                 1469 
                 gggcaactct tccaccagta 
               
               
                   
               
               
                 1470 
                 cctgagaatt gggaacatgc 
               
               
                   
               
               
                 1471 
                 ttgctgctct tttccaggtt 
               
               
                   
               
               
                 1472 
                 agcagcctct cgctcactca c 
               
               
                   
               
               
                 1473 
                 ttccaaagca gcctctcgct c 
               
               
                   
               
               
                 1474 
                 ttcttccaaa gcagcctctc g 
               
               
                   
               
               
                 1475 
                 agtttcttcc aaagcagcct c 
               
               
                   
               
               
                 1476 
                 tttcttccaa agcagcctct c 
               
               
                   
               
               
                 1477 
                 gtttcttcca aagcagcctc t 
               
               
                   
               
               
                 1478 
                 gagtttcttc caaagcagcc t 
               
               
                   
               
               
                 1479 
                 tgagtttctt ccaaagcagc c 
               
               
                   
               
               
                 1480 
                 gcagccucuc gcucacucac c 
               
               
                   
               
               
                 1481 
                 ccaaagcagc cucucgcuca c 
               
               
                   
               
               
                 1482 
                 uucuuccaaa gcagccucuc g 
               
               
                   
               
               
                 1483 
                 aucuaugagu uucuuccaaa g 
               
               
                   
               
               
                 1484 
                 uguugcagua aucuaugagu u 
               
               
                   
               
               
                 1485 
                 cagggggaac uguugcagua a 
               
               
                   
               
               
                 1486 
                 uuuccagguc cagggggaac u 
               
               
                   
               
               
                 1487 
                 gcaagaaacu uuuccagguc c 
               
               
                   
               
               
                 1488 
                 uguaagccag gcaagaaacu u 
               
               
                   
               
               
                 1489 
                 uuucagcuuc uguaagccag g 
               
               
                   
               
               
                 1490 
                 uuggcaguug uuucagcuuc u 
               
               
                   
               
               
                 1491 
                 cuguaggaca uuggcaguug u 
               
               
                   
               
               
                 1492 
                 ggguagcauc cuguaggaca u 
               
               
                   
               
               
                 1493 
                 cuuuccuuac ggguagcauc c 
               
               
                   
               
               
                 1494 
                 uucuaggagc cuuuccuuac g 
               
               
                   
               
               
                 1495 
                 ccuuggaguc uucuaggagc c 
               
               
                   
               
               
                 1496 
                 ucuuuuacuc ccuuggaguc u 
               
               
                   
               
               
                 1497 
                 uuucaucagc ucuuuuacuc c 
               
               
                   
               
               
                 1498 
                 uugccauugu uucaucagcu 
               
               
                   
               
               
                 1499 
                 uccuguagga cauuggcagu 
               
               
                   
               
               
                 1500 
                 catggaagga gggtccctat 
               
               
                   
               
               
                 1501 
                 ctgccggctt aattcatcat 
               
               
                   
               
               
                 1502 
                 ataatgaaaa cgccgccatt t 
               
               
                   
               
               
                 1503 
                 tcataatgaa aacgccgcca t 
               
               
                   
               
               
                 1504 
                 atcataatga aaacgccgcc a 
               
               
                   
               
               
                 1505 
                 tatcataatg aaaacgccgc c 
               
               
                   
               
               
                 1506 
                 atatcataat gaaaacgccg c 
               
               
                   
               
               
                 1507 
                 tatatcataa tgaaaacgcc g 
               
               
                   
               
               
                 1508 
                 ttatatcata atgaaaacgc c 
               
               
                   
               
               
                 1509 
                 tgaaaacgcc gccatttctc aacagatctg 
               
               
                   
               
               
                 1510 
                 atcataatga aaacgccgcc 
               
               
                   
               
               
                 1511 
                 tatcataatg aaaacgccgc 
               
               
                   
               
               
                 1512 
                 tatcataatg aaaacgccgc c 
               
               
                   
               
               
                 1513 
                 cucaacagau cugucaaauc gc 
               
               
                   
               
               
                 1514 
                 gccgccauuu cucaacagau cu 
               
               
                   
               
               
                 1515 
                 uaaugaaaac gccgccauuu cu 
               
               
                   
               
               
                 1516 
                 uaucauaaug aaaacgccgc ca 
               
               
                   
               
               
                 1517 
                 cuuuauauca uaaugaaaac gc 
               
               
                   
               
               
                 1518 
                 gauuaaauau cuuuauauca ua 
               
               
                   
               
               
                 1519 
                 guuagccacu gauuaaauau cu 
               
               
                   
               
               
                 1520 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 1521 
                 ugagaaacug uucagcuucu gu 
               
               
                   
               
               
                 1522 
                 ugugucuuuc ugagaaacug uu 
               
               
                   
               
               
                 1523 
                 guucccaauu cucaggaauu ug 
               
               
                   
               
               
                 1524 
                 uauuuagcau guucccaauu cu 
               
               
                   
               
               
                 1525 
                 auaccauuug uauuuagcau gu 
               
               
                   
               
               
                 1526 
                 ucagcuucug uuagccacug 
               
               
                   
               
               
                 1527 
                 tccagtatac ttacaggctc c 
               
               
                   
               
               
                 1528 
                 atccagtata cttacaggct c 
               
               
                   
               
               
                 1529 
                 gatccagtat acttacaggc t 
               
               
                   
               
               
                 1530 
                 ggatccagta tacttacagg c 
               
               
                   
               
               
                 1531 
                 gggatccagt atacttacag g 
               
               
                   
               
               
                 1532 
                 cttacaggct ccaatagtgg tcagt 
               
               
                   
               
               
                 1533 
                 gggatccagt atacttacag gctcc 
               
               
                   
               
               
                 1534 
                 aacaaccgga tgtggaagag 
               
               
                   
               
               
                 1535 
                 ttggagatgg cagtttcctt 
               
               
                   
               
               
                 1536 
                 cauuucucaa cagaucuguc aa 
               
               
                   
               
               
                 1537 
                 aaaacgccgc cauuucucaa ca 
               
               
                   
               
               
                 1538 
                 aauaucuuua uaucauaaug aa 
               
               
                   
               
               
                 1539 
                 cuucuguuag ccacugauua aa 
               
               
                   
               
               
                 1540 
                 aacuguucag cuucuguuag cc 
               
               
                   
               
               
                 1541 
                 cuuucugaga aacuguucag cu 
               
               
                   
               
               
                 1542 
                 gaauuugugu cuuucugaga aa 
               
               
                   
               
               
                 1543 
                 cucaggaauu ugugucuuuc ug 
               
               
                   
               
               
                 1544 
                 caauucucag gaauuugugu cu 
               
               
                   
               
               
                 1545 
                 agcauguucc caauucucag ga 
               
               
                   
               
               
                 1546 
                 gagtcttcta ggagcctt 
               
               
                   
               
               
                 1547 
                 gtttcttcca aagcagcctc 
               
               
                   
               
               
                 1548 
                 agtttcttcc aaagcagcct 
               
               
                   
               
               
                 1549 
                 agtttcttcc aaagcagcct c 
               
               
                   
               
               
                 1550 
                 ggatccagta tacttacagg 
               
               
                   
               
               
                 1551 
                 gggatccagt atacttacag 
               
               
                   
               
               
                 1552 
                 tgggatccag tatacttaca g 
               
               
                   
               
               
                 1553 
                 atgggatcca gtatacttac a 
               
               
                   
               
               
                 1554 
                 guggcuaaca gaagcu 
               
               
                   
               
               
                 1555 
                 gggaacaugc uaaauac 
               
               
                   
               
               
                 1556 
                 agacacaaau uccugaga 
               
               
                   
               
               
                 1557 
                 cuguugagaa a 
               
               
                   
               
               
                 1558 
                 ucagcuucug uuagccacug 
               
               
                   
               
               
                 1559 
                 uucagcuucu guuagccacu 
               
               
                   
               
               
                 1560 
                 uucagcuucu guuagccacu g 
               
               
                   
               
               
                 1561 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 1562 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 1563 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 1564 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 1565 
                 ucagcuucug uuagccacug au 
               
               
                   
               
               
                 1566 
                 uucagcuucu guuagccacu gau 
               
               
                   
               
               
                 1567 
                 ucagcuucug uuagccacug auu 
               
               
                   
               
               
                 1568 
                 uucagcuucu guuagccacu gauu 
               
               
                   
               
               
                 1569 
                 ucagcuucug uuagccacug auua 
               
               
                   
               
               
                 1570 
                 uucagcuucu guuagccacu gaua 
               
               
                   
               
               
                 1571 
                 ucagcuucug uuagccacug auuaa 
               
               
                   
               
               
                 1572 
                 uucagcuucu guuagccacu gauuaa 
               
               
                   
               
               
                 1573 
                 ucagcuucug uuagccacug auuaaa 
               
               
                   
               
               
                 1574 
                 uucagcuucu guuagccacu gauuaaa 
               
               
                   
               
               
                 1575 
                 cagcuucugu uagccacug 
               
               
                   
               
               
                 1576 
                 cagcuucugu uagccacuga u 
               
               
                   
               
               
                 1577 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 1578 
                 cagcuucugu uagccacuga uu 
               
               
                   
               
               
                 1579 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 1580 
                 cagcuucugu uagccacuga uua 
               
               
                   
               
               
                 1581 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 1582 
                 cagcuucugu uagccacuga uuaa 
               
               
                   
               
               
                 1583 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 1584 
                 cagcuucugu uagccacuga uuaaa 
               
               
                   
               
               
                 1585 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 1586 
                 agcuucuguu agccacugau 
               
               
                   
               
               
                 1587 
                 gcuucuguua gccacugauu 
               
               
                   
               
               
                 1588 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 1589 
                 gcuucuguua gccacugauu a 
               
               
                   
               
               
                 1590 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 1591 
                 gcuucuguua gccacugauu aa 
               
               
                   
               
               
                 1592 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 1593 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 1594 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 1595 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 1596 
                 ccauuuguau uuagcauguu ccc 
               
               
                   
               
               
                 1597 
                 agauaccauu uguauuuagc 
               
               
                   
               
               
                 1598 
                 gccauuucuc aacagaucu 
               
               
                   
               
               
                 1599 
                 gccauuucuc aacagaucug uca 
               
               
                   
               
               
                 1600 
                 auucucagga auuugugucu uuc 
               
               
                   
               
               
                 1601 
                 ucucaggaau uugugucuuu c 
               
               
                   
               
               
                 1602 
                 guucagcuuc uguuagcc 
               
               
                   
               
               
                 1603 
                 cugauuaaau aucuuuauau c 
               
               
                   
               
               
                 1604 
                 gccgccauuu cucaacag 
               
               
                   
               
               
                 1605 
                 guauuuagca uguuccca 
               
               
                   
               
               
                 1606 
                 caggaauuug ugucuuuc 
               
               
                   
               
               
                 1607 
                 ucuguuagcc acugauuaaa u 
               
               
                   
               
               
                 1608 
                 cgaccugagc uuuguuguag 
               
               
                   
               
               
                 1609 
                 cgaccugagc uuuguuguag acuau 
               
               
                   
               
               
                 1610 
                 ccugagcuuu guuguagacu auc 
               
               
                   
               
               
                 1611 
                 cguugcacuu ugcaaugcug cug 
               
               
                   
               
               
                 1612 
                 cuguagcuuc acccuuucc 
               
               
                   
               
               
                 1613 
                 gagagagcuu ccuguagcuu cacc 
               
               
                   
               
               
                 1614 
                 guccuuguac auuuuguuaa cuuuuuc 
               
               
                   
               
               
                 1615 
                 ucagcuucug uuagccacug 
               
               
                   
               
               
                 1616 
                 uucagcuucu guuagccacu 
               
               
                   
               
               
                 1617 
                 uucagcuucu guuagccacu g 
               
               
                   
               
               
                 1618 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 1619 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 1620 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 1621 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 1622 
                 ucagcuucug uuagccacug au 
               
               
                   
               
               
                 1623 
                 uucagcuucu guuagccacu gau 
               
               
                   
               
               
                 1624 
                 ucagcuucug uuagccacug auu 
               
               
                   
               
               
                 1625 
                 uucagcuucu guuagccacu gauu 
               
               
                   
               
               
                 1626 
                 ucagcuucug uuagccacug auua 
               
               
                   
               
               
                 1627 
                 uucagcuucu guuagccacu gaua 
               
               
                   
               
               
                 1628 
                 ucagcuucug uuagccacug auuaa 
               
               
                   
               
               
                 1629 
                 uucagcuucu guuagccacu gauuaa 
               
               
                   
               
               
                 1630 
                 ucagcuucug uuagccacug auuaaa 
               
               
                   
               
               
                 1631 
                 uucagcuucu guuagccacu gauuaaa 
               
               
                   
               
               
                 1632 
                 cagcuucugu uagccacug 
               
               
                   
               
               
                 1633 
                 cagcuucugu uagccacuga u 
               
               
                   
               
               
                 1634 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 1635 
                 cagcuucugu uagccacuga uu 
               
               
                   
               
               
                 1636 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 1637 
                 cagcuucugu uagccacuga uua 
               
               
                   
               
               
                 1638 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 1639 
                 cagcuucugu uagccacuga uuaa 
               
               
                   
               
               
                 1640 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 1641 
                 cagcuucugu uagccacuga uuaaa 
               
               
                   
               
               
                 1642 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 1643 
                 agcuucuguu agccacugau 
               
               
                   
               
               
                 1644 
                 gcuucuguua gccacugauu 
               
               
                   
               
               
                 1645 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 1646 
                 gcuucuguua gccacugauu a 
               
               
                   
               
               
                 1647 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 1648 
                 gcuucuguua gccacugauu aa 
               
               
                   
               
               
                 1649 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 1650 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 1651 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 1652 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 1653 
                 ccauuuguau uuagcauguu ccc 
               
               
                   
               
               
                 1654 
                 agauaccauu uguauuuagc 
               
               
                   
               
               
                 1655 
                 gccauuucuc aacagaucu 
               
               
                   
               
               
                 1656 
                 gccauuucuc aacagaucug uca 
               
               
                   
               
               
                 1657 
                 auucucagga auuugugucu uuc 
               
               
                   
               
               
                 1658 
                 ucucaggaau uugugucuuu c 
               
               
                   
               
               
                 1659 
                 guucagcuuc uguuagcc 
               
               
                   
               
               
                 1660 
                 cugauuaaau aucuuuauau c 
               
               
                   
               
               
                 1661 
                 gccgccauuu cucaacag 
               
               
                   
               
               
                 1662 
                 guauuuagca uguuccca 
               
               
                   
               
               
                 1663 
                 caggaauuug ugucuuuc 
               
               
                   
               
               
                 1664 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 1665 
                 auucaauguu cugacaacag uuugc 
               
               
                   
               
               
                 1666 
                 ccaguugcau ucaauguucu gacaa 
               
               
                   
               
               
                 1667 
                 caguugcauu caauguucug ac 
               
               
                   
               
               
                 1668 
                 aguugcauuc aauguucuga 
               
               
                   
               
               
                 1669 
                 gauugcugaa uuauuucuuc c 
               
               
                   
               
               
                 1670 
                 gauugcugaa uuauuucuuc cccag 
               
               
                   
               
               
                 1671 
                 auugcugaau uauuucuucc ccagu 
               
               
                   
               
               
                 1672 
                 uugcugaauu auuucuuccc caguu 
               
               
                   
               
               
                 1673 
                 ugcugaauua uuucuucccc aguug 
               
               
                   
               
               
                 1674 
                 gcugaauuau uucuucccca guugc 
               
               
                   
               
               
                 1675 
                 cugaauuauu ucuuccccag uugca 
               
               
                   
               
               
                 1676 
                 ugaauuauuu cuuccccagu ugcau 
               
               
                   
               
               
                 1677 
                 gaauuauuuc uuccccaguu gcauu 
               
               
                   
               
               
                 1678 
                 aauuauuucu uccccaguug cauuc 
               
               
                   
               
               
                 1679 
                 auuauuucuu ccccaguugc auuca 
               
               
                   
               
               
                 1680 
                 uuauuucuuc cccaguugca uucaa 
               
               
                   
               
               
                 1681 
                 uauuucuucc ccaguugcau ucaau 
               
               
                   
               
               
                 1682 
                 auuucuuccc caguugcauu caaug 
               
               
                   
               
               
                 1683 
                 uuucuucccc aguugcauuc aaugu 
               
               
                   
               
               
                 1684 
                 uucuucccca guugcauuca auguu 
               
               
                   
               
               
                 1685 
                 ucuuccccag uugcauucaa uguuc 
               
               
                   
               
               
                 1686 
                 cuuccccagu ugcauucaau guucu 
               
               
                   
               
               
                 1687 
                 uuccccaguu gcauucaaug uucug 
               
               
                   
               
               
                 1688 
                 uccccaguug cauucaaugu ucuga 
               
               
                   
               
               
                 1689 
                 ccccaguugc auucaauguu cugac 
               
               
                   
               
               
                 1690 
                 cccaguugca uucaauguuc ugaca 
               
               
                   
               
               
                 1691 
                 ccaguugcau ucaauguucu gacaa 
               
               
                   
               
               
                 1692 
                 caguugcauu caauguucug acaac 
               
               
                   
               
               
                 1693 
                 aguugcauuc aauguucuga caaca 
               
               
                   
               
               
                 1694 
                 guugcauuca auguucugac aacag 
               
               
                   
               
               
                 1695 
                 uugcauucaa uguucugaca acagu 
               
               
                   
               
               
                 1696 
                 ugcauucaau guucugacaa caguu 
               
               
                   
               
               
                 1697 
                 gcauucaaug uucugacaac aguuu 
               
               
                   
               
               
                 1698 
                 cauucaaugu ucugacaaca guuug 
               
               
                   
               
               
                 1699 
                 auucaauguu cugacaacag uuugc 
               
               
                   
               
               
                 1700 
                 ucaauguucu gacaacaguu ugccg 
               
               
                   
               
               
                 1701 
                 caauguucug acaacaguuu gccgc 
               
               
                   
               
               
                 1702 
                 aauguucuga caacaguuug ccgcu 
               
               
                   
               
               
                 1703 
                 auguucugac aacaguuugc cgcug 
               
               
                   
               
               
                 1704 
                 uguucugaca acaguuugcc gcugc 
               
               
                   
               
               
                 1705 
                 guucugacaa caguuugccg cugcc 
               
               
                   
               
               
                 1706 
                 uucugacaac aguuugccgc ugccc 
               
               
                   
               
               
                 1707 
                 ucugacaaca guuugccgcu gccca 
               
               
                   
               
               
                 1708 
                 cugacaacag uuugccgcug cccaa 
               
               
                   
               
               
                 1709 
                 ugacaacagu uugccgcugc ccaau 
               
               
                   
               
               
                 1710 
                 gacaacaguu ugccgcugcc caaug 
               
               
                   
               
               
                 1711 
                 acaacaguuu gccgcugccc aaugc 
               
               
                   
               
               
                 1712 
                 caacaguuug ccgcugccca augcc 
               
               
                   
               
               
                 1713 
                 aacaguuugc cgcugcccaa ugcca 
               
               
                   
               
               
                 1714 
                 acaguuugcc gcugcccaau gccau 
               
               
                   
               
               
                 1715 
                 caguuugccg cugcccaaug ccauc 
               
               
                   
               
               
                 1716 
                 aguuugccgc ugcccaaugc caucc 
               
               
                   
               
               
                 1717 
                 guuugccgcu gcccaaugcc auccu 
               
               
                   
               
               
                 1718 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 1719 
                 uugccgcugc ccaaugccau ccugg 
               
               
                   
               
               
                 1720 
                 ugccgcugcc caaugccauc cugga 
               
               
                   
               
               
                 1721 
                 gccgcugccc aaugccaucc uggag 
               
               
                   
               
               
                 1722 
                 ccgcugccca augccauccu ggagu 
               
               
                   
               
               
                 1723 
                 cgcugcccaa ugccauccug gaguu 
               
               
                   
               
               
                 1724 
                 gcuuuucuuu uaguugcugc ucuuu 
               
               
                   
               
               
                 1725 
                 cuuuucuuuu aguugcugcu cuuuu 
               
               
                   
               
               
                 1726 
                 uuuucuuuua guugcugcuc uuuuc 
               
               
                   
               
               
                 1727 
                 uuucuuuuag uugcugcucu uuucc 
               
               
                   
               
               
                 1728 
                 uucuuuuagu ugcugcucuu uucca 
               
               
                   
               
               
                 1729 
                 ucuuuuaguu gcugcucuuu uccag 
               
               
                   
               
               
                 1730 
                 cuuuuaguug cugcucuuuu ccagg 
               
               
                   
               
               
                 1731 
                 uuuuaguugc ugcucuuuuc caggu 
               
               
                   
               
               
                 1732 
                 uuuaguugcu gcucuuuucc agguu 
               
               
                   
               
               
                 1733 
                 uuaguugcug cucuuuucca gguuc 
               
               
                   
               
               
                 1734 
                 uaguugcugc ucuuuuccag guuca 
               
               
                   
               
               
                 1735 
                 aguugcugcu cuuuuccagg uucaa 
               
               
                   
               
               
                 1736 
                 guugcugcuc uuuuccaggu ucaag 
               
               
                   
               
               
                 1737 
                 uugcugcucu uuuccagguu caagu 
               
               
                   
               
               
                 1738 
                 ugcugcucuu uuccagguuc aagug 
               
               
                   
               
               
                 1739 
                 gcugcucuuu uccagguuca agugg 
               
               
                   
               
               
                 1740 
                 cugcucuuuu ccagguucaa guggg 
               
               
                   
               
               
                 1741 
                 ugcucuuuuc cagguucaag uggga 
               
               
                   
               
               
                 1742 
                 gcucuuuucc agguucaagu gggac 
               
               
                   
               
               
                 1743 
                 cucuuuucca gguucaagug ggaua 
               
               
                   
               
               
                 1744 
                 ucuuuuccag guucaagugg gauac 
               
               
                   
               
               
                 1745 
                 cuuuuccagg uucaaguggg auacu 
               
               
                   
               
               
                 1746 
                 uuuuccaggu ucaaguggga uacua 
               
               
                   
               
               
                 1747 
                 uuuccagguu caagugggau acuag 
               
               
                   
               
               
                 1748 
                 uuccagguuc aagugggaua cuagc 
               
               
                   
               
               
                 1749 
                 uccagguuca agugggauac uagca 
               
               
                   
               
               
                 1750 
                 ccagguucaa gugggauacu agcaa 
               
               
                   
               
               
                 1751 
                 cagguucaag ugggauacua gcaau 
               
               
                   
               
               
                 1752 
                 agguucaagu gggauacuag caaug 
               
               
                   
               
               
                 1753 
                 gguucaagug ggauacuagc aaugu 
               
               
                   
               
               
                 1754 
                 guucaagugg gauacuagca auguu 
               
               
                   
               
               
                 1755 
                 uucaaguggg auacuagcaa uguua 
               
               
                   
               
               
                 1756 
                 ucaaguggga uacuagcaau guuau 
               
               
                   
               
               
                 1757 
                 caagugggau acuagcaaug uuauc 
               
               
                   
               
               
                 1758 
                 aagugggaua cuagcaaugu uaucu 
               
               
                   
               
               
                 1759 
                 agugggauac uagcaauguu aucug 
               
               
                   
               
               
                 1760 
                 gugggauacu agcaauguua ucugc 
               
               
                   
               
               
                 1761 
                 ugggauacua gcaauguuau cugcu 
               
               
                   
               
               
                 1762 
                 gggauacuag caauguuauc ugcuu 
               
               
                   
               
               
                 1763 
                 ggauacuagc aauguuaucu gcuuc 
               
               
                   
               
               
                 1764 
                 gauacuagca auguuaucug cuucc 
               
               
                   
               
               
                 1765 
                 auacuagcaa uguuaucugc uuccu 
               
               
                   
               
               
                 1766 
                 uacuagcaau guuaucugcu uccuc 
               
               
                   
               
               
                 1767 
                 acuagcaaug uuaucugcuu ccucc 
               
               
                   
               
               
                 1768 
                 cuagcaaugu uaucugcuuc cucca 
               
               
                   
               
               
                 1769 
                 uagcaauguu aucugcuucc uccaa 
               
               
                   
               
               
                 1770 
                 agcaauguua ucugcuuccu ccaac 
               
               
                   
               
               
                 1771 
                 gcaauguuau cugcuuccuc caacc 
               
               
                   
               
               
                 1772 
                 caauguuauc ugcuuccucc aacca 
               
               
                   
               
               
                 1773 
                 aauguuaucu gcuuccucca accau 
               
               
                   
               
               
                 1774 
                 auguuaucug cuuccuccaa ccaua 
               
               
                   
               
               
                 1775 
                 uguuaucugc uuccuccaac cauaa 
               
               
                   
               
               
                 1776 
                 guuaucugcu uccuccaacc auaaa 
               
               
                   
               
               
                 1777 
                 gcugcucuuu uccagguuc 
               
               
                   
               
               
                 1778 
                 ucuuuuccag guucaagugg 
               
               
                   
               
               
                 1779 
                 agguucaagu gggauacua 
               
               
                   
               
               
                 1780 
                 cucagcucuu gaaguaaacg 
               
               
                   
               
               
                 1781 
                 ccucagcucu ugaaguaaac 
               
               
                   
               
               
                 1782 
                 ccucagcucu ugaaguaaac g 
               
               
                   
               
               
                 1783 
                 auagugguca guccaggagc u 
               
               
                   
               
               
                 1784 
                 caguccagga gcuaggucag g 
               
               
                   
               
               
                 1785 
                 uaguggucag uccaggagcu agguc 
               
               
                   
               
               
                 1786 
                 agagcaggua ccuccaacau caagg 
               
               
                   
               
               
                 1787 
                 gagcagguac cuccaacauc aagga 
               
               
                   
               
               
                 1788 
                 agcagguacc uccaacauca aggaa 
               
               
                   
               
               
                 1789 
                 gcagguaccu ccaacaucaa ggaag 
               
               
                   
               
               
                 1790 
                 cagguaccuc caacaucaag gaaga 
               
               
                   
               
               
                 1791 
                 agguaccucc aacaucaagg aagau 
               
               
                   
               
               
                 1792 
                 gguaccucca acaucaagga agaug 
               
               
                   
               
               
                 1793 
                 guaccuccaa caucaaggaa gaugg 
               
               
                   
               
               
                 1794 
                 uaccuccaac aucaaggaag auggc 
               
               
                   
               
               
                 1795 
                 accuccaaca ucaaggaaga uggca 
               
               
                   
               
               
                 1796 
                 ccuccaacau caaggaagau ggcau 
               
               
                   
               
               
                 1797 
                 cuccaacauc aaggaagaug gcauu 
               
               
                   
               
               
                 1798 
                 cuccaacauc aaggaagaug gcauuucuag 
               
               
                   
               
               
                 1799 
                 uccaacauca aggaagaugg cauuu 
               
               
                   
               
               
                 1800 
                 ccaacaucaa ggaagauggc auuuc 
               
               
                   
               
               
                 1801 
                 caacaucaag gaagauggca uuucu 
               
               
                   
               
               
                 1802 
                 aacaucaagg aagauggcau uucua 
               
               
                   
               
               
                 1803 
                 acaucaagga agauggcauu ucuag 
               
               
                   
               
               
                 1804 
                 acaucaagga agauggcauu ucuaguuugg 
               
               
                   
               
               
                 1805 
                 acaucaagga agauggcauu ucuag 
               
               
                   
               
               
                 1806 
                 caucaaggaa gauggcauuu cuagu 
               
               
                   
               
               
                 1807 
                 aucaaggaag auggcauuuc uaguu 
               
               
                   
               
               
                 1808 
                 ucaaggaaga uggcauuucu aguuu 
               
               
                   
               
               
                 1809 
                 ucaaggaaga uggcauuucu 
               
               
                   
               
               
                 1810 
                 caaggaagau ggcauuucua guuug 
               
               
                   
               
               
                 1811 
                 aaggaagaug gcauuucuag uuugg 
               
               
                   
               
               
                 1812 
                 aggaagaugg cauuucuagu uugga 
               
               
                   
               
               
                 1813 
                 ggaagauggc auuucuaguu uggag 
               
               
                   
               
               
                 1814 
                 gaagauggca uuucuaguuu ggaga 
               
               
                   
               
               
                 1815 
                 aagauggcau uucuaguuug gagau 
               
               
                   
               
               
                 1816 
                 agauggcauu ucuaguuugg agaug 
               
               
                   
               
               
                 1817 
                 gauggcauuu cuaguuugga gaugg 
               
               
                   
               
               
                 1818 
                 auggcauuuc uaguuuggag auggc 
               
               
                   
               
               
                 1819 
                 uggcauuucu aguuuggaga uggca 
               
               
                   
               
               
                 1820 
                 ggcauuucua guuuggagau ggcag 
               
               
                   
               
               
                 1821 
                 gcauuucuag uuuggagaug gcagu 
               
               
                   
               
               
                 1822 
                 cauuucuagu uuggagaugg caguu 
               
               
                   
               
               
                 1823 
                 auuucuaguu uggagauggc aguuu 
               
               
                   
               
               
                 1824 
                 uuucuaguuu ggagauggca guuuc 
               
               
                   
               
               
                 1825 
                 uucuaguuug gagauggcag uuucc 
               
               
                   
               
               
                 1826 
                 ccucuugauu gcuggucuug uuuuu 
               
               
                   
               
               
                 1827 
                 cucuugauug cuggucuugu uuuuc 
               
               
                   
               
               
                 1828 
                 ucuugauugc uggucuuguu uuuca 
               
               
                   
               
               
                 1829 
                 cuugauugcu ggucuuguuu uucaa 
               
               
                   
               
               
                 1830 
                 uugauugcug gucuuguuuu ucaaa 
               
               
                   
               
               
                 1831 
                 ugauugcugg ucuuguuuuu caaau 
               
               
                   
               
               
                 1832 
                 gauugcuggu cuuguuuuuc aaauu 
               
               
                   
               
               
                 1833 
                 auugcugguc uuguuuuuca aauuu 
               
               
                   
               
               
                 1834 
                 uugcuggucu uguuuuucaa auuuu 
               
               
                   
               
               
                 1835 
                 ugcuggucuu guuuuucaaa uuuug 
               
               
                   
               
               
                 1836 
                 gcuggucuug uuuuucaaau uuugg 
               
               
                   
               
               
                 1837 
                 cuggucuugu uuuucaaauu uuggg 
               
               
                   
               
               
                 1838 
                 uggucuuguu uuucaaauuu ugggc 
               
               
                   
               
               
                 1839 
                 ggucuuguuu uucaaauuuu gggca 
               
               
                   
               
               
                 1840 
                 gucuuguuuu ucaaauuuug ggcag 
               
               
                   
               
               
                 1841 
                 ucuuguuuuu caaauuuugg gcagc 
               
               
                   
               
               
                 1842 
                 cuuguuuuuc aaauuuuggg cagcg 
               
               
                   
               
               
                 1843 
                 uuguuuuuca aauuuugggc agcgg 
               
               
                   
               
               
                 1844 
                 uguuuuucaa auuuugggca gcggu 
               
               
                   
               
               
                 1845 
                 guuuuucaaa uuuugggcag cggua 
               
               
                   
               
               
                 1846 
                 uuuuucaaau uuugggcagc gguaa 
               
               
                   
               
               
                 1847 
                 uuuucaaauu uugggcagcg guaau 
               
               
                   
               
               
                 1848 
                 uuucaaauuu ugggcagcgg uaaug 
               
               
                   
               
               
                 1849 
                 uucaaauuuu gggcagcggu aauga 
               
               
                   
               
               
                 1850 
                 ucaaauuuug ggcagcggua augag 
               
               
                   
               
               
                 1851 
                 caaauuuugg gcagcgguaa ugagu 
               
               
                   
               
               
                 1852 
                 aaauuuuggg cagcgguaau gaguu 
               
               
                   
               
               
                 1853 
                 aauuuugggc agcgguaaug aguuc 
               
               
                   
               
               
                 1854 
                 auuuugggca gcgguaauga guucu 
               
               
                   
               
               
                 1855 
                 ccauuguguu gaauccuuua acauu 
               
               
                   
               
               
                 1856 
                 ccauuguguu gaauccuuua ac 
               
               
                   
               
               
                 1857 
                 auuguguuga auccuuuaac 
               
               
                   
               
               
                 1858 
                 ccuguccuaa gaccugcuca 
               
               
                   
               
               
                 1859 
                 cuuuuggauu gcaucuacug uauag 
               
               
                   
               
               
                 1860 
                 cauucaacug uugccuccgg uucug 
               
               
                   
               
               
                 1861 
                 cuguugccuc cgguucugaa ggug 
               
               
                   
               
               
                 1862 
                 cauucaacug uugccuccgg uucugaaggu g 
               
               
                   
               
               
                 1863 
                 cugaaggugu ucuuguacuu caucc 
               
               
                   
               
               
                 1864 
                 uguauaggga cccuccuucc augacuc 
               
               
                   
               
               
                 1865 
                 aucccacuga uucugaauuc 
               
               
                   
               
               
                 1866 
                 uuggcucugg ccuguccuaa ga 
               
               
                   
               
               
                 1867 
                 aagaccugcu cagcuucuuc cuuagcuucc agcca 
               
               
                   
               
               
                 1868 
                 ggagagagcu uccuguagcu 
               
               
                   
               
               
                 1869 
                 ucacccuuuc cacaggcguu gca 
               
               
                   
               
               
                 1870 
                 ugcacuuugc aaugcugcug ucuucuugcu au 
               
               
                   
               
               
                 1871 
                 ucauaaugaa aacgccgcca uuucucaaca gaucu 
               
               
                   
               
               
                 1872 
                 uuugugucuu ucugagaaac 
               
               
                   
               
               
                 1873 
                 uuuagcaugu ucccaauucu caggaauuug 
               
               
                   
               
               
                 1874 
                 uccuguagaa uacuggcauc 
               
               
                   
               
               
                 1875 
                 ugcagaccuc cugccaccgc agauuca 
               
               
                   
               
               
                 1876 
                 uugcagaccu ccugccaccg cagauucagg cuuc 
               
               
                   
               
               
                 1877 
                 uguuuuugag gauugcugaa 
               
               
                   
               
               
                 1878 
                 uguucugaca acaguuugcc gcugcccaau gccauccugg 
               
               
                   
               
               
                 1879 
                 cucuuuucca gguucaagug ggauacuagc 
               
               
                   
               
               
                 1880 
                 caagcuuuuc uuuuaguugc ugcucuuuuc c 
               
               
                   
               
               
                 1881 
                 uauucuuuug uucuucuagc cuggagaaag 
               
               
                   
               
               
                 1882 
                 cugcuuccuc caaccauaaa acaaauuc 
               
               
                   
               
               
                 1883 
                 ccacucagag cucagaucuu cuaacuucc 
               
               
                   
               
               
                 1884 
                 cuuccacuca gagcucagau cuucuaa 
               
               
                   
               
               
                 1885 
                 caguccagga gcuaggucag gcugcuuugc 
               
               
                   
               
               
                 1886 
                 ucuugaagua aacgguuuac cgccuuccac ucagagc 
               
               
                   
               
               
                 1887 
                 uccaacuggg gacgccucug uuccaaaucc 
               
               
                   
               
               
                 1888 
                 acuggggacg ccucuguucc a 
               
               
                   
               
               
                 1889 
                 ccguaaugau uguucuagcc 
               
               
                   
               
               
                 1890 
                 uuuugggcag cgguaaugag uucuu 
               
               
                   
               
               
                 1891 
                 uuugggcagc gguaaugagu ucuuc 
               
               
                   
               
               
                 1892 
                 uugggcagcg guaaugaguu cuucc 
               
               
                   
               
               
                 1893 
                 ugggcagcgg uaaugaguuc uucca 
               
               
                   
               
               
                 1894 
                 gggcagcggu aaugaguucu uccaa 
               
               
                   
               
               
                 1895 
                 ggcagcggua augaguucuu ccaac 
               
               
                   
               
               
                 1896 
                 gcagcgguaa ugaguucuuc caacu 
               
               
                   
               
               
                 1897 
                 cagcgguaau gaguucuucc aacug 
               
               
                   
               
               
                 1898 
                 agcgguaaug aguucuucca acugg 
               
               
                   
               
               
                 1899 
                 gcgguaauga guucuuccaa cuggg 
               
               
                   
               
               
                 1900 
                 cgguaaugag uucuuccaac ugggg 
               
               
                   
               
               
                 1901 
                 gguaaugagu ucuuccaacu gggga 
               
               
                   
               
               
                 1902 
                 guaaugaguu cuuccaacug gggac 
               
               
                   
               
               
                 1903 
                 uaaugaguuc uuccaacugg ggacg 
               
               
                   
               
               
                 1904 
                 aaugaguucu uccaacuggg gacgc 
               
               
                   
               
               
                 1905 
                 augaguucuu ccaacugggg acgcc 
               
               
                   
               
               
                 1906 
                 ugaguucuuc caacugggga cgccu 
               
               
                   
               
               
                 1907 
                 gaguucuucc aacuggggac gccuc 
               
               
                   
               
               
                 1908 
                 aguucuucca acuggggacg ccucu 
               
               
                   
               
               
                 1909 
                 guucuuccaa cuggggacgc cucug 
               
               
                   
               
               
                 1910 
                 uucuuccaac uggggacgcc ucugu 
               
               
                   
               
               
                 1911 
                 ucuuccaacu ggggacgccu cuguu 
               
               
                   
               
               
                 1912 
                 cuuccaacug gggacgccuc uguuc 
               
               
                   
               
               
                 1913 
                 uuccaacugg ggacgccucu guucc 
               
               
                   
               
               
                 1914 
                 gauugcuggu cuuguuuuuc 
               
               
                   
               
               
                 1915 
                 ccucuugauu gcuggucuug 
               
               
                   
               
               
                 1916 
                 gguaaugagu ucuuccaacu gg 
               
               
                   
               
               
                 1917 
                 acuggggacg ccucuguucc 
               
               
                   
               
               
                 1918 
                 ucaaggaaga uggcauuucu 
               
               
                   
               
               
                 1919 
                 ggccaaaccu cggcuuaccu 
               
               
                   
               
               
                 1920 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 1921 
                 auucaauguu cugacaacag uuugc 
               
               
                   
               
               
                 1922 
                 ccaguugcau ucaauguucu gacaa 
               
               
                   
               
               
                 1923 
                 caguugcauu caauguucug ac 
               
               
                   
               
               
                 1924 
                 aguugcauuc aauguucuga 
               
               
                   
               
               
                 1925 
                 gauugcugaa uuauuucuuc c 
               
               
                   
               
               
                 1926 
                 gauugcugaa uuauuucuuc cccag 
               
               
                   
               
               
                 1927 
                 auugcugaau uauuucuucc ccagu 
               
               
                   
               
               
                 1928 
                 uugcugaauu auuucuuccc caguu 
               
               
                   
               
               
                 1929 
                 ugcugaauua uuucuucccc aguug 
               
               
                   
               
               
                 1930 
                 gcugaauuau uucuucccca guugc 
               
               
                   
               
               
                 1931 
                 cugaauuauu ucuuccccag uugca 
               
               
                   
               
               
                 1932 
                 ugaauuauuu cuuccccagu ugcau 
               
               
                   
               
               
                 1933 
                 gaauuauuuc uuccccaguu gcauu 
               
               
                   
               
               
                 1934 
                 aauuauuucu uccccaguug cauuc 
               
               
                   
               
               
                 1935 
                 auuauuucuu ccccaguugc auuca 
               
               
                   
               
               
                 1936 
                 uuauuucuuc cccaguugca uucaa 
               
               
                   
               
               
                 1937 
                 uauuucuucc ccaguugcau ucaau 
               
               
                   
               
               
                 1938 
                 auuucuuccc caguugcauu caaug 
               
               
                   
               
               
                 1939 
                 uuucuucccc aguugcauuc aaugu 
               
               
                   
               
               
                 1940 
                 uucuucccca guugcauuca auguu 
               
               
                   
               
               
                 1941 
                 ucuuccccag uugcauucaa uguuc 
               
               
                   
               
               
                 1942 
                 cuuccccagu ugcauucaau guucu 
               
               
                   
               
               
                 1943 
                 uuccccaguu gcauucaaug uucug 
               
               
                   
               
               
                 1944 
                 uccccaguug cauucaaugu ucuga 
               
               
                   
               
               
                 1945 
                 ccccaguugc auucaauguu cugac 
               
               
                   
               
               
                 1946 
                 cccaguugca uucaauguuc ugaca 
               
               
                   
               
               
                 1947 
                 ccaguugcau ucaauguucu gacaa 
               
               
                   
               
               
                 1948 
                 caguugcauu caauguucug acaac 
               
               
                   
               
               
                 1949 
                 aguugcauuc aauguucuga caaca 
               
               
                   
               
               
                 1950 
                 uccuguagaa uacuggcauc 
               
               
                   
               
               
                 1951 
                 ugcagaccuc cugccaccgc agauuca 
               
               
                   
               
               
                 1952 
                 uugcagaccu ccugccaccg cagauucagg cuuc 
               
               
                   
               
               
                 1953 
                 guugcauuca auguucugac aacag 
               
               
                   
               
               
                 1954 
                 uugcauucaa uguucugaca acagu 
               
               
                   
               
               
                 1955 
                 ugcauucaau guucugacaa caguu 
               
               
                   
               
               
                 1956 
                 gcauucaaug uucugacaac aguuu 
               
               
                   
               
               
                 1957 
                 cauucaaugu ucugacaaca guuug 
               
               
                   
               
               
                 1958 
                 auucaauguu cugacaacag uuugc 
               
               
                   
               
               
                 1959 
                 ucaauguucu gacaacaguu ugccg 
               
               
                   
               
               
                 1960 
                 caauguucug acaacaguuu gccgc 
               
               
                   
               
               
                 1961 
                 aauguucuga caacaguuug ccgcu 
               
               
                   
               
               
                 1962 
                 auguucugac aacaguuugc cgcug 
               
               
                   
               
               
                 1963 
                 uguucugaca acaguuugcc gcugc 
               
               
                   
               
               
                 1964 
                 guucugacaa caguuugccg cugcc 
               
               
                   
               
               
                 1965 
                 uucugacaac aguuugccgc ugccc 
               
               
                   
               
               
                 1966 
                 ucugacaaca guuugccgcu gccca 
               
               
                   
               
               
                 1967 
                 cugacaacag uuugccgcug cccaa 
               
               
                   
               
               
                 1968 
                 ugacaacagu uugccgcugc ccaau 
               
               
                   
               
               
                 1969 
                 gacaacaguu ugccgcugcc caaug 
               
               
                   
               
               
                 1970 
                 acaacaguuu gccgcugccc aaugc 
               
               
                   
               
               
                 1971 
                 caacaguuug ccgcugccca augcc 
               
               
                   
               
               
                 1972 
                 aacaguuugc cgcugcccaa ugcca 
               
               
                   
               
               
                 1973 
                 acaguuugcc gcugcccaau gccau 
               
               
                   
               
               
                 1974 
                 caguuugccg cugcccaaug ccauc 
               
               
                   
               
               
                 1975 
                 aguuugccgc ugcccaaugc caucc 
               
               
                   
               
               
                 1976 
                 guuugccgcu gcccaaugcc auccu 
               
               
                   
               
               
                 1977 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 1978 
                 uugccgcugc ccaaugccau ccugg 
               
               
                   
               
               
                 1979 
                 ugccgcugcc caaugccauc cugga 
               
               
                   
               
               
                 1980 
                 gccgcugccc aaugccaucc uggag 
               
               
                   
               
               
                 1981 
                 ccgcugccca augccauccu ggagu 
               
               
                   
               
               
                 1982 
                 cgcugcccaa ugccauccug gaguu 
               
               
                   
               
               
                 1983 
                 uguuuuugag gauugcugaa 
               
               
                   
               
               
                 1984 
                 uguucugaca acaguuugcc gcugcccaau gccauccugg 
               
               
                   
               
               
                 1985 
                 gcccaaugcc auccugg 
               
               
                   
               
               
                 1986 
                 agagcaggua ccuccaacau caagg 
               
               
                   
               
               
                 1987 
                 gagcagguac cuccaacauc aagga 
               
               
                   
               
               
                 1988 
                 agcagguacc uccaacauca aggaa 
               
               
                   
               
               
                 1989 
                 gcagguaccu ccaacaucaa ggaag 
               
               
                   
               
               
                 1990 
                 cagguaccuc caacaucaag gaaga 
               
               
                   
               
               
                 1991 
                 agguaccucc aacaucaagg aagau 
               
               
                   
               
               
                 1992 
                 gguaccucca acaucaagga agaug 
               
               
                   
               
               
                 1993 
                 guaccuccaa caucaaggaa gaugg 
               
               
                   
               
               
                 1994 
                 uaccuccaac aucaaggaag auggc 
               
               
                   
               
               
                 1995 
                 accuccaaca ucaaggaaga uggca 
               
               
                   
               
               
                 1996 
                 ccuccaacau caaggaagau ggcau 
               
               
                   
               
               
                 1997 
                 cuccaacauc aaggaagaug gcauu 
               
               
                   
               
               
                 1998 
                 cuccaacauc aaggaagaug gcauuucuag 
               
               
                   
               
               
                 1999 
                 uccaacauca aggaagaugg cauuu 
               
               
                   
               
               
                 2000 
                 ccaacaucaa ggaagauggc auuuc 
               
               
                   
               
               
                 2001 
                 caacaucaag gaagauggca uuucu 
               
               
                   
               
               
                 2002 
                 aacaucaagg aagauggcau uucua 
               
               
                   
               
               
                 2003 
                 acaucaagga agauggcauu ucuag 
               
               
                   
               
               
                 2004 
                 acaucaagga agauggcauu ucuaguuugg 
               
               
                   
               
               
                 2005 
                 acaucaagga agauggcauu ucuag 
               
               
                   
               
               
                 2006 
                 caucaaggaa gauggcauuu cuagu 
               
               
                   
               
               
                 2007 
                 aucaaggaag auggcauuuc uaguu 
               
               
                   
               
               
                 2008 
                 ucaaggaaga uggcauuucu aguuu 
               
               
                   
               
               
                 2009 
                 ucaaggaaga uggcauuucu 
               
               
                   
               
               
                 2010 
                 caaggaagau ggcauuucua guuug 
               
               
                   
               
               
                 2011 
                 aaggaagaug gcauuucuag uuugg 
               
               
                   
               
               
                 2012 
                 aggaagaugg cauuucuagu uugga 
               
               
                   
               
               
                 2013 
                 ggaagauggc auuucuaguu uggag 
               
               
                   
               
               
                 2014 
                 gaagauggca uuucuaguuu ggaga 
               
               
                   
               
               
                 2015 
                 aagauggcau uucuaguuug gagau 
               
               
                   
               
               
                 2016 
                 agauggcauu ucuaguuugg agaug 
               
               
                   
               
               
                 2017 
                 gauggcauuu cuaguuugga gaugg 
               
               
                   
               
               
                 2018 
                 auggcauuuc uaguuuggag auggc 
               
               
                   
               
               
                 2019 
                 uggcauuucu aguuuggaga uggca 
               
               
                   
               
               
                 2020 
                 ggcauuucua guuuggagau ggcag 
               
               
                   
               
               
                 2021 
                 gcauuucuag uuuggagaug gcagu 
               
               
                   
               
               
                 2022 
                 cauuucuagu uuggagaugg caguu 
               
               
                   
               
               
                 2023 
                 auuucuaguu uggagauggc aguuu 
               
               
                   
               
               
                 2024 
                 uuucuaguuu ggagauggca guuuc 
               
               
                   
               
               
                 2025 
                 uucuaguuug gagauggcag uuucc 
               
               
                   
               
               
                 2026 
                 ccauuguguu gaauccuuua acauu 
               
               
                   
               
               
                 2027 
                 ccauuguguu gaauccuuua ac 
               
               
                   
               
               
                 2028 
                 auuguguuga auccuuuaac 
               
               
                   
               
               
                 2029 
                 ccuguccuaa gaccugcuca 
               
               
                   
               
               
                 2030 
                 cuuuuggauu gcaucuacug uauag 
               
               
                   
               
               
                 2031 
                 cauucaacug uugccuccgg uucug 
               
               
                   
               
               
                 2032 
                 cuguugccuc cgguucugaa ggug 
               
               
                   
               
               
                 2033 
                 cauucaacug uugccuccgg uucugaaggu g 
               
               
                   
               
               
                 2034 
                 cugaaggugu ucuuguacuu caucc 
               
               
                   
               
               
                 2035 
                 uguauaggga cccuccuucc augacuc 
               
               
                   
               
               
                 2036 
                 aucccacuga uucugaauuc 
               
               
                   
               
               
                 2037 
                 uuggcucugg ccuguccuaa ga 
               
               
                   
               
               
                 2038 
                 aagaccugcu cagcuucuuc cuuagcuucc agcca 
               
               
                   
               
               
                 2039 
                 ugcauguucc agucguugug ugg 
               
               
                   
               
               
                 2040 
                 cacuauucca gucaaauagg ucugg 
               
               
                   
               
               
                 2041 
                 auuuaccaac cuucaggauc gagua 
               
               
                   
               
               
                 2042 
                 ggccuaaaac acauacacau a 
               
               
                   
               
               
                 2043 
                 ucagcuucug uuagccacug 
               
               
                   
               
               
                 2044 
                 uucagcuucu guuagccacu 
               
               
                   
               
               
                 2045 
                 uucagcuucu guuagccacu g 
               
               
                   
               
               
                 2046 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 2047 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 2048 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 2049 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 2050 
                 ucagcuucug uuagccacug au 
               
               
                   
               
               
                 2051 
                 uucagcuucu guuagccacu gau 
               
               
                   
               
               
                 2052 
                 ucagcuucug uuagccacug auu 
               
               
                   
               
               
                 2053 
                 uucagcuucu guuagccacu gauu 
               
               
                   
               
               
                 2054 
                 ucagcuucug uuagccacug auua 
               
               
                   
               
               
                 2055 
                 uucagcuucu guuagccacu gaua 
               
               
                   
               
               
                 2056 
                 ucagcuucug uuagccacug auuaa 
               
               
                   
               
               
                 2057 
                 uucagcuucu guuagccacu gauuaa 
               
               
                   
               
               
                 2058 
                 ucagcuucug uuagccacug auuaaa 
               
               
                   
               
               
                 2059 
                 uucagcuucu guuagccacu gauuaaa 
               
               
                   
               
               
                 2060 
                 cagcuucugu uagccacug 
               
               
                   
               
               
                 2061 
                 cagcuucugu uagccacuga u 
               
               
                   
               
               
                 2062 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 2063 
                 cagcuucugu uagccacuga uu 
               
               
                   
               
               
                 2064 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 2065 
                 cagcuucugu uagccacuga uua 
               
               
                   
               
               
                 2066 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 2067 
                 cagcuucugu uagccacuga uuaa 
               
               
                   
               
               
                 2068 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 2069 
                 cagcuucugu uagccacuga uuaaa 
               
               
                   
               
               
                 2070 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 2071 
                 agcuucuguu agccacugau 
               
               
                   
               
               
                 2072 
                 gcuucuguua gccacugauu 
               
               
                   
               
               
                 2073 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 2074 
                 gcuucuguua gccacugauu a 
               
               
                   
               
               
                 2075 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 2076 
                 gcuucuguua gccacugauu aa 
               
               
                   
               
               
                 2077 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 2078 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 2079 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 2080 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 2081 
                 ccauuuguau uuagcauguu ccc 
               
               
                   
               
               
                 2082 
                 agauaccauu uguauuuagc 
               
               
                   
               
               
                 2083 
                 gccauuucuc aacagaucu 
               
               
                   
               
               
                 2084 
                 gccauuucuc aacagaucug uca 
               
               
                   
               
               
                 2085 
                 auucucagga auuugugucu uuc 
               
               
                   
               
               
                 2086 
                 ucucaggaau uugugucuuu c 
               
               
                   
               
               
                 2087 
                 guucagcuuc uguuagcc 
               
               
                   
               
               
                 2088 
                 cugauuaaau aucuuuauau c 
               
               
                   
               
               
                 2089 
                 gccgccauuu cucaacag 
               
               
                   
               
               
                 2090 
                 guauuuagca uguuccca 
               
               
                   
               
               
                 2091 
                 caggaauuug ugucuuuc 
               
               
                   
               
               
                 2092 
                 gcuuuucuuu uaguugcugc ucuuu 
               
               
                   
               
               
                 2093 
                 cuuuucuuuu aguugcugcu cuuuu 
               
               
                   
               
               
                 2094 
                 uuuucuuuua guugcugcuc uuuuc 
               
               
                   
               
               
                 2095 
                 uuucuuuuag uugcugcucu uuucc 
               
               
                   
               
               
                 2096 
                 uucuuuuagu ugcugcucuu uucca 
               
               
                   
               
               
                 2097 
                 ucuuuuaguu gcugcucuuu uccag 
               
               
                   
               
               
                 2098 
                 cuuuuaguug cugcucuuuu ccagg 
               
               
                   
               
               
                 2099 
                 uuuuaguugc ugcucuuuuc caggu 
               
               
                   
               
               
                 2100 
                 uuuaguugcu gcucuuuucc agguu 
               
               
                   
               
               
                 2101 
                 uuaguugcug cucuuuucca gguuc 
               
               
                   
               
               
                 2102 
                 uaguugcugc ucuuuuccag guuca 
               
               
                   
               
               
                 2103 
                 aguugcugcu cuuuuccagg uucaa 
               
               
                   
               
               
                 2104 
                 guugcugcuc uuuuccaggu ucaag 
               
               
                   
               
               
                 2105 
                 uugcugcucu uuuccagguu caagu 
               
               
                   
               
               
                 2106 
                 ugcugcucuu uuccagguuc aagug 
               
               
                   
               
               
                 2107 
                 gcugcucuuu uccagguuca agugg 
               
               
                   
               
               
                 2108 
                 cugcucuuuu ccagguucaa guggg 
               
               
                   
               
               
                 2109 
                 ugcucuuuuc cagguucaag uggga 
               
               
                   
               
               
                 2110 
                 gcucuuuucc agguucaagu gggac 
               
               
                   
               
               
                 2111 
                 cucuuuucca gguucaagug ggaua 
               
               
                   
               
               
                 2112 
                 ucuuuuccag guucaagugg gauac 
               
               
                   
               
               
                 2113 
                 cuuuuccagg uucaaguggg auacu 
               
               
                   
               
               
                 2114 
                 uuuuccaggu ucaaguggga uacua 
               
               
                   
               
               
                 2115 
                 uuuccagguu caagugggau acuag 
               
               
                   
               
               
                 2116 
                 uuccagguuc aagugggaua cuagc 
               
               
                   
               
               
                 2117 
                 uccagguuca agugggauac uagca 
               
               
                   
               
               
                 2118 
                 ccagguucaa gugggauacu agcaa 
               
               
                   
               
               
                 2119 
                 cagguucaag ugggauacua gcaau 
               
               
                   
               
               
                 2120 
                 agguucaagu gggauacuag caaug 
               
               
                   
               
               
                 2121 
                 gguucaagug ggauacuagc aaugu 
               
               
                   
               
               
                 2122 
                 guucaagugg gauacuagca auguu 
               
               
                   
               
               
                 2123 
                 uucaaguggg auacuagcaa uguua 
               
               
                   
               
               
                 2124 
                 ucaaguggga uacuagcaau guuau 
               
               
                   
               
               
                 2125 
                 caagugggau acuagcaaug uuauc 
               
               
                   
               
               
                 2126 
                 aagugggaua cuagcaaugu uaucu 
               
               
                   
               
               
                 2127 
                 agugggauac uagcaauguu aucug 
               
               
                   
               
               
                 2128 
                 gugggauacu agcaauguua ucugc 
               
               
                   
               
               
                 2129 
                 ugggauacua gcaauguuau cugcu 
               
               
                   
               
               
                 2130 
                 gggauacuag caauguuauc ugcuu 
               
               
                   
               
               
                 2131 
                 ggauacuagc aauguuaucu gcuuc 
               
               
                   
               
               
                 2132 
                 gauacuagca auguuaucug cuucc 
               
               
                   
               
               
                 2133 
                 auacuagcaa uguuaucugc uuccu 
               
               
                   
               
               
                 2134 
                 uacuagcaau guuaucugcu uccuc 
               
               
                   
               
               
                 2135 
                 acuagcaaug uuaucugcuu ccucc 
               
               
                   
               
               
                 2136 
                 cuagcaaugu uaucugcuuc cucca 
               
               
                   
               
               
                 2137 
                 uagcaauguu aucugcuucc uccaa 
               
               
                   
               
               
                 2138 
                 agcaauguua ucugcuuccu ccaac 
               
               
                   
               
               
                 2139 
                 gcaauguuau cugcuuccuc caacc 
               
               
                   
               
               
                 2140 
                 caauguuauc ugcuuccucc aacca 
               
               
                   
               
               
                 2141 
                 aauguuaucu gcuuccucca accau 
               
               
                   
               
               
                 2142 
                 auguuaucug cuuccuccaa ccaua 
               
               
                   
               
               
                 2143 
                 uguuaucugc uuccuccaac cauaa 
               
               
                   
               
               
                 2144 
                 guuaucugcu uccuccaacc auaaa 
               
               
                   
               
               
                 2145 
                 gcugcucuuu uccagguuc 
               
               
                   
               
               
                 2146 
                 ucuuuuccag guucaagugg 
               
               
                   
               
               
                 2147 
                 agguucaagu gggauacua 
               
               
                   
               
               
                 2148 
                 caauuuuucc cacucaguau u 
               
               
                   
               
               
                 2149 
                 uugaaguucc uggagucuu 
               
               
                   
               
               
                 2150 
                 uccucaggag gcagcucuaa au 
               
               
                   
               
               
                 2151 
                 gcgcugguca caaaauccug uugaac 
               
               
                   
               
               
                 2152 
                 cacuugcuug aaaaggucua caaagga 
               
               
                   
               
               
                 2153 
                 ggugaauaac uuacaaauuu ggaagc 
               
               
                   
               
               
                 2154 
                 ccacaggcgu ugcacuuugc aaugc 
               
               
                   
               
               
                 2155 
                 cacaggcguu gcacuuugca augcu 
               
               
                   
               
               
                 2156 
                 acaggcguug cacuuugcaa ugcug 
               
               
                   
               
               
                 2157 
                 caggcguugc acuuugcaau gcugc 
               
               
                   
               
               
                 2158 
                 aggcguugca cuuugcaaug cugcu 
               
               
                   
               
               
                 2159 
                 ggcguugcac uuugcaaugc ugcug 
               
               
                   
               
               
                 2160 
                 gcguugcacu uugcaaugcu gcugu 
               
               
                   
               
               
                 2161 
                 cguugcacuu ugcaaugcug cuguc 
               
               
                   
               
               
                 2162 
                 cguugcacuu ugcaaugcug cug 
               
               
                   
               
               
                 2163 
                 guugcacuuu gcaaugcugc ugucu 
               
               
                   
               
               
                 2164 
                 uugcacuuug caaugcugcu gucuu 
               
               
                   
               
               
                 2165 
                 ugcacuuugc aaugcugcug ucuuc 
               
               
                   
               
               
                 2166 
                 gcacuuugca augcugcugu cuucu 
               
               
                   
               
               
                 2167 
                 cacuuugcaa ugcugcuguc uucuu 
               
               
                   
               
               
                 2168 
                 acuuugcaau gcugcugucu ucuug 
               
               
                   
               
               
                 2169 
                 cuuugcaaug cugcugucuu cuugc 
               
               
                   
               
               
                 2170 
                 uuugcaaugc ugcugucuuc uugcu 
               
               
                   
               
               
                 2171 
                 uugcaaugcu gcugucuucu ugcua 
               
               
                   
               
               
                 2172 
                 ugcaaugcug cugucuucuu gcuau 
               
               
                   
               
               
                 2173 
                 gcaaugcugc ugucuucuug cuaug 
               
               
                   
               
               
                 2174 
                 caaugcugcu gucuucuugc uauga 
               
               
                   
               
               
                 2175 
                 aaugcugcug ucuucuugcu augaa 
               
               
                   
               
               
                 2176 
                 augcugcugu cuucuugcua ugaau 
               
               
                   
               
               
                 2177 
                 ugcugcuguc uucuugcuau gaaua 
               
               
                   
               
               
                 2178 
                 gcugcugucu ucuugcuaug aauaa 
               
               
                   
               
               
                 2179 
                 cugcugucuu cuugcuauga auaau 
               
               
                   
               
               
                 2180 
                 ugcugucuuc uugcuaugaa uaaug 
               
               
                   
               
               
                 2181 
                 gcugucuucu ugcuaugaau aaugu 
               
               
                   
               
               
                 2182 
                 cugucuucuu gcuaugaaua auguc 
               
               
                   
               
               
                 2183 
                 ugucuucuug cuaugaauaa uguca 
               
               
                   
               
               
                 2184 
                 gucuucuugc uaugaauaau gucaa 
               
               
                   
               
               
                 2185 
                 ucuucuugcu augaauaaug ucaau 
               
               
                   
               
               
                 2186 
                 cuucuugcua ugaauaaugu caauc 
               
               
                   
               
               
                 2187 
                 uucuugcuau gaauaauguc aaucc 
               
               
                   
               
               
                 2188 
                 ucuugcuaug aauaauguca auccg 
               
               
                   
               
               
                 2189 
                 cuugcuauga auaaugucaa uccga 
               
               
                   
               
               
                 2190 
                 uugcuaugaa uaaugucaau ccgac 
               
               
                   
               
               
                 2191 
                 ugcuaugaau aaugucaauc cgacc 
               
               
                   
               
               
                 2192 
                 gcuaugaaua augucaaucc gaccu 
               
               
                   
               
               
                 2193 
                 cuaugaauaa ugucaauccg accug 
               
               
                   
               
               
                 2194 
                 uaugaauaau gucaauccga ccuga 
               
               
                   
               
               
                 2195 
                 augaauaaug ucaauccgac cugag 
               
               
                   
               
               
                 2196 
                 ugaauaaugu caauccgacc ugagc 
               
               
                   
               
               
                 2197 
                 gaauaauguc aauccgaccu gagcu 
               
               
                   
               
               
                 2198 
                 aauaauguca auccgaccug agcuu 
               
               
                   
               
               
                 2199 
                 auaaugucaa uccgaccuga gcuuu 
               
               
                   
               
               
                 2200 
                 uaaugucaau ccgaccugag cuuug 
               
               
                   
               
               
                 2201 
                 aaugucaauc cgaccugagc uuugu 
               
               
                   
               
               
                 2202 
                 augucaaucc gaccugagcu uuguu 
               
               
                   
               
               
                 2203 
                 ugucaauccg accugagcuu uguug 
               
               
                   
               
               
                 2204 
                 gucaauccga ccugagcuuu guugu 
               
               
                   
               
               
                 2205 
                 ucaauccgac cugagcuuug uugua 
               
               
                   
               
               
                 2206 
                 caauccgacc ugagcuuugu uguag 
               
               
                   
               
               
                 2207 
                 aauccgaccu gagcuuuguu guaga 
               
               
                   
               
               
                 2208 
                 auccgaccug agcuuuguug uagac 
               
               
                   
               
               
                 2209 
                 uccgaccuga gcuuuguugu agacu 
               
               
                   
               
               
                 2210 
                 ccgaccugag cuuuguugua gacua 
               
               
                   
               
               
                 2211 
                 cgaccugagc uuuguuguag 
               
               
                   
               
               
                 2212 
                 cgaccugagc uuuguuguag acuau 
               
               
                   
               
               
                 2213 
                 gaccugagcu uuguuguaga cuauc 
               
               
                   
               
               
                 2214 
                 accugagcuu uguuguagac uauca 
               
               
                   
               
               
                 2215 
                 ccugagcuuu guuguagacu auc 
               
               
                   
               
               
                 2216 
                 gcuuuucuuu uaguugcugc ucuuu 
               
               
                   
               
               
                 2217 
                 cuuuucuuuu aguugcugcu cuuuu 
               
               
                   
               
               
                 2218 
                 uuuucuuuua guugcugcuc uuuuc 
               
               
                   
               
               
                 2219 
                 uuucuuuuag uugcugcucu uuucc 
               
               
                   
               
               
                 2220 
                 uucuuuuagu ugcugcucuu uucca 
               
               
                   
               
               
                 2221 
                 ucuuuuaguu gcugcucuuu uccag 
               
               
                   
               
               
                 2222 
                 cuuuuaguug cugcucuuuu ccagg 
               
               
                   
               
               
                 2223 
                 uuuuaguugc ugcucuuuuc caggu 
               
               
                   
               
               
                 2224 
                 uuuaguugcu gcucuuuucc agguu 
               
               
                   
               
               
                 2225 
                 uuaguugcug cucuuuucca gguuc 
               
               
                   
               
               
                 2226 
                 uaguugcugc ucuuuuccag guuca 
               
               
                   
               
               
                 2227 
                 aguugcugcu cuuuuccagg uucaa 
               
               
                   
               
               
                 2228 
                 guugcugcuc uuuuccaggu ucaag 
               
               
                   
               
               
                 2229 
                 uugcugcucu uuuccagguu caagu 
               
               
                   
               
               
                 2230 
                 ugcugcucuu uuccagguuc aagug 
               
               
                   
               
               
                 2231 
                 gcugcucuuu uccagguuca agugg 
               
               
                   
               
               
                 2232 
                 cugcucuuuu ccagguucaa guggg 
               
               
                   
               
               
                 2233 
                 ugcucuuuuc cagguucaag uggga 
               
               
                   
               
               
                 2234 
                 gcucuuuucc agguucaagu gggac 
               
               
                   
               
               
                 2235 
                 cucuuuucca gguucaagug ggaua 
               
               
                   
               
               
                 2236 
                 ucuuuuccag guucaagugg gauac 
               
               
                   
               
               
                 2237 
                 ucuuuuccag guucaagugg 
               
               
                   
               
               
                 2238 
                 cuuuuccagg uucaaguggg auacu 
               
               
                   
               
               
                 2239 
                 uuuuccaggu ucaaguggga uacua 
               
               
                   
               
               
                 2240 
                 uuuccagguu caagugggau acuag 
               
               
                   
               
               
                 2241 
                 uuccagguuc aagugggaua cuagc 
               
               
                   
               
               
                 2242 
                 uccagguuca agugggauac uagca 
               
               
                   
               
               
                 2243 
                 ccagguucaa gugggauacu agcaa 
               
               
                   
               
               
                 2244 
                 cagguucaag ugggauacua gcaau 
               
               
                   
               
               
                 2245 
                 agguucaagu gggauacuag caaug 
               
               
                   
               
               
                 2246 
                 gguucaagug ggauacuagc aaugu 
               
               
                   
               
               
                 2247 
                 guucaagugg gauacuagca auguu 
               
               
                   
               
               
                 2248 
                 uucaaguggg auacuagcaa uguua 
               
               
                   
               
               
                 2249 
                 ucaaguggga uacuagcaau guuau 
               
               
                   
               
               
                 2250 
                 caagugggau acuagcaaug uuauc 
               
               
                   
               
               
                 2251 
                 aagugggaua cuagcaaugu uaucu 
               
               
                   
               
               
                 2252 
                 agugggauac uagcaauguu aucug 
               
               
                   
               
               
                 2253 
                 gugggauacu agcaauguua ucugc 
               
               
                   
               
               
                 2254 
                 ugggauacua gcaauguuau cugcu 
               
               
                   
               
               
                 2255 
                 gggauacuag caauguuauc ugcuu 
               
               
                   
               
               
                 2256 
                 ggauacuagc aauguuaucu gcuuc 
               
               
                   
               
               
                 2257 
                 gauacuagca auguuaucug cuucc 
               
               
                   
               
               
                 2258 
                 auacuagcaa uguuaucugc uuccu 
               
               
                   
               
               
                 2259 
                 uacuagcaau guuaucugcu uccuc 
               
               
                   
               
               
                 2260 
                 acuagcaaug uuaucugcuu ccucc 
               
               
                   
               
               
                 2261 
                 cuagcaaugu uaucugcuuc cucca 
               
               
                   
               
               
                 2262 
                 uagcaauguu aucugcuucc uccaa 
               
               
                   
               
               
                 2263 
                 agcaauguua ucugcuuccu ccaac 
               
               
                   
               
               
                 2264 
                 gcaauguuau cugcuuccuc caacc 
               
               
                   
               
               
                 2265 
                 caauguuauc ugcuuccucc aacca 
               
               
                   
               
               
                 2266 
                 aauguuaucu gcuuccucca accau 
               
               
                   
               
               
                 2267 
                 auguuaucug cuuccuccaa ccaua 
               
               
                   
               
               
                 2268 
                 uguuaucugc uuccuccaac cauaa 
               
               
                   
               
               
                 2269 
                 ccaauagugg ucaguccagg agcua 
               
               
                   
               
               
                 2270 
                 caauaguggu caguccagga gcuag 
               
               
                   
               
               
                 2271 
                 aauagugguc aguccaggag cuagg 
               
               
                   
               
               
                 2272 
                 auagugguca guccaggagc uaggu 
               
               
                   
               
               
                 2273 
                 auagugguca guccaggagc u 
               
               
                   
               
               
                 2274 
                 uaguggucag uccaggagcu agguc 
               
               
                   
               
               
                 2275 
                 aguggucagu ccaggagcua gguca 
               
               
                   
               
               
                 2276 
                 guggucaguc caggagcuag gucag 
               
               
                   
               
               
                 2277 
                 uggucagucc aggagcuagg ucagg 
               
               
                   
               
               
                 2278 
                 ggucagucca ggagcuaggu caggc 
               
               
                   
               
               
                 2279 
                 gucaguccag gagcuagguc aggcu 
               
               
                   
               
               
                 2280 
                 ucaguccagg agcuagguca ggcug 
               
               
                   
               
               
                 2281 
                 caguccagga gcuaggucag gcugc 
               
               
                   
               
               
                 2282 
                 aguccaggag cuaggucagg cugcu 
               
               
                   
               
               
                 2283 
                 guccaggagc uaggucaggc ugcuu 
               
               
                   
               
               
                 2284 
                 uccaggagcu aggucaggcu gcuuu 
               
               
                   
               
               
                 2285 
                 ccaggagcua ggucaggcug cuuug 
               
               
                   
               
               
                 2286 
                 caggagcuag gucaggcugc uuugc 
               
               
                   
               
               
                 2287 
                 aggagcuagg ucaggcugcu uugcc 
               
               
                   
               
               
                 2288 
                 ggagcuaggu caggcugcuu ugccc 
               
               
                   
               
               
                 2289 
                 gagcuagguc aggcugcuuu gcccu 
               
               
                   
               
               
                 2290 
                 agcuagguca ggcugcuuug cccuc 
               
               
                   
               
               
                 2291 
                 gcuaggucag gcugcuuugc ccuca 
               
               
                   
               
               
                 2292 
                 cuaggucagg cugcuuugcc cucag 
               
               
                   
               
               
                 2293 
                 uaggucaggc ugcuuugccc ucagc 
               
               
                   
               
               
                 2294 
                 aggucaggcu gcuuugcccu cagcu 
               
               
                   
               
               
                 2295 
                 ggucaggcug cuuugcccuc agcuc 
               
               
                   
               
               
                 2296 
                 gucaggcugc uuugcccuca gcucu 
               
               
                   
               
               
                 2297 
                 ucaggcugcu uugcccucag cucuu 
               
               
                   
               
               
                 2298 
                 caggcugcuu ugcccucagc ucuug 
               
               
                   
               
               
                 2299 
                 aggcugcuuu gcccucagcu cuuga 
               
               
                   
               
               
                 2300 
                 ggcugcuuug cccucagcuc uugaa 
               
               
                   
               
               
                 2301 
                 gcugcuuugc ccucagcucu ugaag 
               
               
                   
               
               
                 2302 
                 cugcuuugcc cucagcucuu gaagu 
               
               
                   
               
               
                 2303 
                 ugcuuugccc ucagcucuug aagua 
               
               
                   
               
               
                 2304 
                 gcuuugcccu cagcucuuga aguaa 
               
               
                   
               
               
                 2305 
                 cuuugcccuc agcucuugaa guaaa 
               
               
                   
               
               
                 2306 
                 uuugcccuca gcucuugaag uaaac 
               
               
                   
               
               
                 2307 
                 uugcccucag cucuugaagu aaacg 
               
               
                   
               
               
                 2308 
                 ugcccucagc ucuugaagua aacgg 
               
               
                   
               
               
                 2309 
                 gcccucagcu cuugaaguaa acggu 
               
               
                   
               
               
                 2310 
                 cccucagcuc uugaaguaaa cgguu 
               
               
                   
               
               
                 2311 
                 ccucagcucu ugaaguaaac 
               
               
                   
               
               
                 2312 
                 ccucagcucu ugaaguaaac g 
               
               
                   
               
               
                 2313 
                 cucagcucuu gaaguaaacg 
               
               
                   
               
               
                 2314 
                 guaccuccaa caucaaggaa gaugg 
               
               
                   
               
               
                 2315 
                 uaccuccaac aucaaggaag auggc 
               
               
                   
               
               
                 2316 
                 accuccaaca ucaaggaaga uggca 
               
               
                   
               
               
                 2317 
                 ccuccaacau caaggaagau ggcau 
               
               
                   
               
               
                 2318 
                 cuccaacauc aaggaagaug gcauu 
               
               
                   
               
               
                 2319 
                 uccaacauca aggaagaugg cauuu 
               
               
                   
               
               
                 2320 
                 ccaacaucaa ggaagauggc auuuc 
               
               
                   
               
               
                 2321 
                 caacaucaag gaagauggca uuucu 
               
               
                   
               
               
                 2322 
                 aacaucaagg aagauggcau uucua 
               
               
                   
               
               
                 2323 
                 acaucaagga agauggcauu ucuag 
               
               
                   
               
               
                 2324 
                 caucaaggaa gauggcauuu cuagu 
               
               
                   
               
               
                 2325 
                 aucaaggaag auggcauuuc uaguu 
               
               
                   
               
               
                 2326 
                 ucaaggaaga uggcauuucu aguuu 
               
               
                   
               
               
                 2327 
                 caaggaagau ggcauuucua guuug 
               
               
                   
               
               
                 2328 
                 aaggaagaug gcauuucuag uuugg 
               
               
                   
               
               
                 2329 
                 aggaagaugg cauuucuagu uugga 
               
               
                   
               
               
                 2330 
                 ggaagauggc auuucuaguu uggag 
               
               
                   
               
               
                 2331 
                 gaagauggca uuucuaguuu ggaga 
               
               
                   
               
               
                 2332 
                 aagauggcau uucuaguuug gagau 
               
               
                   
               
               
                 2333 
                 agauggcauu ucuaguuugg agaug 
               
               
                   
               
               
                 2334 
                 gauggcauuu cuaguuugga gaugg 
               
               
                   
               
               
                 2335 
                 auggcauuuc uaguuuggag auggc 
               
               
                   
               
               
                 2336 
                 uggcauuucu aguuuggaga uggca 
               
               
                   
               
               
                 2337 
                 ggcauuucua guuuggagau ggcag 
               
               
                   
               
               
                 2338 
                 gcauuucuag uuuggagaug gcagu 
               
               
                   
               
               
                 2339 
                 cauuucuagu uuggagaugg caguu 
               
               
                   
               
               
                 2340 
                 auuucuaguu uggagauggc aguuu 
               
               
                   
               
               
                 2341 
                 uuucuaguuu ggagauggca guuuc 
               
               
                   
               
               
                 2342 
                 uucuaguuug gagauggcag uuucc 
               
               
                   
               
               
                 2343 
                 ucuaguuugg agauggcagu uuccu 
               
               
                   
               
               
                 2344 
                 cuaguuugga gauggcaguu uccuu 
               
               
                   
               
               
                 2345 
                 uaguuuggag auggcaguuu ccuua 
               
               
                   
               
               
                 2346 
                 aguuuggaga uggcaguuuc cuuag 
               
               
                   
               
               
                 2347 
                 guuuggagau ggcaguuucc uuagu 
               
               
                   
               
               
                 2348 
                 uuuggagaug gcaguuuccu uagua 
               
               
                   
               
               
                 2349 
                 uuggagaugg caguuuccuu aguaa 
               
               
                   
               
               
                 2350 
                 uggagauggc aguuuccuua guaac 
               
               
                   
               
               
                 2351 
                 gagauggcag uuuccuuagu aacca 
               
               
                   
               
               
                 2352 
                 agauggcagu uuccuuagua accac 
               
               
                   
               
               
                 2353 
                 gauggcaguu uccuuaguaa ccaca 
               
               
                   
               
               
                 2354 
                 auggcaguuu ccuuaguaac cacag 
               
               
                   
               
               
                 2355 
                 uggcaguuuc cuuaguaacc acagg 
               
               
                   
               
               
                 2356 
                 ggcaguuucc uuaguaacca caggu 
               
               
                   
               
               
                 2357 
                 gcaguuuccu uaguaaccac agguu 
               
               
                   
               
               
                 2358 
                 caguuuccuu aguaaccaca gguug 
               
               
                   
               
               
                 2359 
                 aguuuccuua guaaccacag guugu 
               
               
                   
               
               
                 2360 
                 guuuccuuag uaaccacagg uugug 
               
               
                   
               
               
                 2361 
                 uuuccuuagu aaccacaggu ugugu 
               
               
                   
               
               
                 2362 
                 uuccuuagua accacagguu guguc 
               
               
                   
               
               
                 2363 
                 uccuuaguaa ccacagguug uguca 
               
               
                   
               
               
                 2364 
                 ccuuaguaac cacagguugu gucac 
               
               
                   
               
               
                 2365 
                 cuuaguaacc acagguugug ucacc 
               
               
                   
               
               
                 2366 
                 uuaguaacca cagguugugu cacca 
               
               
                   
               
               
                 2367 
                 uaguaaccac agguuguguc accag 
               
               
                   
               
               
                 2368 
                 aguaaccaca gguuguguca ccaga 
               
               
                   
               
               
                 2369 
                 guaaccacag guugugucac cagag 
               
               
                   
               
               
                 2370 
                 uaaccacagg uugugucacc agagu 
               
               
                   
               
               
                 2371 
                 aaccacaggu ugugucacca gagua 
               
               
                   
               
               
                 2372 
                 accacagguu gugucaccag aguaa 
               
               
                   
               
               
                 2373 
                 ccacagguug ugucaccaga guaac 
               
               
                   
               
               
                 2374 
                 cacagguugu gucaccagag uaaca 
               
               
                   
               
               
                 2375 
                 acagguugug ucaccagagu aacag 
               
               
                   
               
               
                 2376 
                 cagguugugu caccagagua acagu 
               
               
                   
               
               
                 2377 
                 agguuguguc accagaguaa caguc 
               
               
                   
               
               
                 2378 
                 gguuguguca ccagaguaac agucu 
               
               
                   
               
               
                 2379 
                 guugugucac cagaguaaca gucug 
               
               
                   
               
               
                 2380 
                 uugugucacc agaguaacag ucuga 
               
               
                   
               
               
                 2381 
                 ugugucacca gaguaacagu cugag 
               
               
                   
               
               
                 2382 
                 gugucaccag aguaacaguc ugagu 
               
               
                   
               
               
                 2383 
                 ugucaccaga guaacagucu gagua 
               
               
                   
               
               
                 2384 
                 gucaccagag uaacagucug aguag 
               
               
                   
               
               
                 2385 
                 ucaccagagu aacagucuga guagg 
               
               
                   
               
               
                 2386 
                 caccagagua acagucugag uagga 
               
               
                   
               
               
                 2387 
                 accagaguaa cagucugagu aggag 
               
               
                   
               
               
                 2388 
                 agccucuuga uugcuggucu uguuu 
               
               
                   
               
               
                 2389 
                 gccucuugau ugcuggucuu guuuu 
               
               
                   
               
               
                 2390 
                 ccucuugauu gcuggucuug uuuuu 
               
               
                   
               
               
                 2391 
                 ccucuugauu gcuggucuug 
               
               
                   
               
               
                 2392 
                 cucuugauug cuggucuugu uuuuc 
               
               
                   
               
               
                 2393 
                 ucuugauugc uggucuuguu uuuca 
               
               
                   
               
               
                 2394 
                 cuugauugcu ggucuuguuu uucaa 
               
               
                   
               
               
                 2395 
                 uugauugcug gucuuguuuu ucaaa 
               
               
                   
               
               
                 2396 
                 ugauugcugg ucuuguuuuu caaau 
               
               
                   
               
               
                 2397 
                 gauugcuggu cuuguuuuuc aaauu 
               
               
                   
               
               
                 2398 
                 gauugcuggu cuuguuuuuc 
               
               
                   
               
               
                 2399 
                 auugcugguc uuguuuuuca aauuu 
               
               
                   
               
               
                 2400 
                 uugcuggucu uguuuuucaa auuuu 
               
               
                   
               
               
                 2401 
                 ugcuggucuu guuuuucaaa uuuug 
               
               
                   
               
               
                 2402 
                 gcuggucuug uuuuucaaau uuugg 
               
               
                   
               
               
                 2403 
                 cuggucuugu uuuucaaauu uuggg 
               
               
                   
               
               
                 2404 
                 uggucuuguu uuucaaauuu ugggc 
               
               
                   
               
               
                 2405 
                 ggucuuguuu uucaaauuuu gggca 
               
               
                   
               
               
                 2406 
                 gucuuguuuu ucaaauuuug ggcag 
               
               
                   
               
               
                 2407 
                 ucuuguuuuu caaauuuugg gcagc 
               
               
                   
               
               
                 2408 
                 cuuguuuuuc aaauuuuggg cagcg 
               
               
                   
               
               
                 2409 
                 uuguuuuuca aauuuugggc agcgg 
               
               
                   
               
               
                 2410 
                 uguuuuucaa auuuugggca gcggu 
               
               
                   
               
               
                 2411 
                 guuuuucaaa uuuugggcag cggua 
               
               
                   
               
               
                 2412 
                 uuuuucaaau uuugggcagc gguaa 
               
               
                   
               
               
                 2413 
                 uuuucaaauu uugggcagcg guaau 
               
               
                   
               
               
                 2414 
                 uuucaaauuu ugggcagcgg uaaug 
               
               
                   
               
               
                 2415 
                 uucaaauuuu gggcagcggu aauga 
               
               
                   
               
               
                 2416 
                 ucaaauuuug ggcagcggua augag 
               
               
                   
               
               
                 2417 
                 caaauuuugg gcagcgguaa ugagu 
               
               
                   
               
               
                 2418 
                 aaauuuuggg cagcgguaau gaguu 
               
               
                   
               
               
                 2419 
                 aauuuugggc agcgguaaug aguuc 
               
               
                   
               
               
                 2420 
                 auuuugggca gcgguaauga guucu 
               
               
                   
               
               
                 2421 
                 uuuugggcag cgguaaugag uucuu 
               
               
                   
               
               
                 2422 
                 uuugggcagc gguaaugagu ucuuc 
               
               
                   
               
               
                 2423 
                 uugggcagcg guaaugaguu cuucc 
               
               
                   
               
               
                 2424 
                 ugggcagcgg uaaugaguuc uucca 
               
               
                   
               
               
                 2425 
                 gggcagcggu aaugaguucu uccaa 
               
               
                   
               
               
                 2426 
                 ggcagcggua augaguucuu ccaac 
               
               
                   
               
               
                 2427 
                 gcagcgguaa ugaguucuuc caacu 
               
               
                   
               
               
                 2428 
                 cagcgguaau gaguucuucc aacug 
               
               
                   
               
               
                 2429 
                 agcgguaaug aguucuucca acugg 
               
               
                   
               
               
                 2430 
                 gcgguaauga guucuuccaa cuggg 
               
               
                   
               
               
                 2431 
                 cgguaaugag uucuuccaac ugggg 
               
               
                   
               
               
                 2432 
                 gguaaugagu ucuuccaacu gggga 
               
               
                   
               
               
                 2433 
                 gguaaugagu ucuuccaacu gg 
               
               
                   
               
               
                 2434 
                 guaaugaguu cuuccaacug gggac 
               
               
                   
               
               
                 2435 
                 uaaugaguuc uuccaacugg ggacg 
               
               
                   
               
               
                 2436 
                 aaugaguucu uccaacuggg gacgc 
               
               
                   
               
               
                 2437 
                 augaguucuu ccaacugggg acgcc 
               
               
                   
               
               
                 2438 
                 ugaguucuuc caacugggga cgccu 
               
               
                   
               
               
                 2439 
                 gaguucuucc aacuggggac gccuc 
               
               
                   
               
               
                 2440 
                 aguucuucca acuggggacg ccucu 
               
               
                   
               
               
                 2441 
                 guucuuccaa cuggggacgc cucug 
               
               
                   
               
               
                 2442 
                 uucuuccaac uggggacgcc ucugu 
               
               
                   
               
               
                 2443 
                 ucuuccaacu ggggacgccu cuguu 
               
               
                   
               
               
                 2444 
                 cuuccaacug gggacgccuc uguuc 
               
               
                   
               
               
                 2445 
                 uuccaacugg ggacgccucu guucc 
               
               
                   
               
               
                 2446 
                 uccaacuggg gacgccucug uucca 
               
               
                   
               
               
                 2447 
                 ccaacugggg acgccucugu uccaa 
               
               
                   
               
               
                 2448 
                 caacugggga cgccucuguu ccaaa 
               
               
                   
               
               
                 2449 
                 aacuggggac gccucuguuc caaau 
               
               
                   
               
               
                 2450 
                 acuggggacg ccucuguucc aaauc 
               
               
                   
               
               
                 2451 
                 cuggggacgc cucuguucca aaucc 
               
               
                   
               
               
                 2452 
                 uggggacgcc ucuguuccaa auccu 
               
               
                   
               
               
                 2453 
                 ggggacgccu cuguuccaaa uccug 
               
               
                   
               
               
                 2454 
                 gggacgccuc uguuccaaau ccugc 
               
               
                   
               
               
                 2455 
                 ggacgccucu guuccaaauc cugca 
               
               
                   
               
               
                 2456 
                 gacgccucug uuccaaaucc ugcau 
               
               
                   
               
               
                 2457 
                 cucuggccug uccuaagacc ugcuc 
               
               
                   
               
               
                 2458 
                 ucuggccugu ccuaagaccu gcuca 
               
               
                   
               
               
                 2459 
                 uggccugucc uaagaccugc ucagc 
               
               
                   
               
               
                 2460 
                 ggccuguccu aagaccugcu cagcu 
               
               
                   
               
               
                 2461 
                 gccuguccua agaccugcuc agcuu 
               
               
                   
               
               
                 2462 
                 ccuguccuaa gaccugcuca gcuuc 
               
               
                   
               
               
                 2463 
                 cuguccuaag accugcucag cuucu 
               
               
                   
               
               
                 2464 
                 uguccuaaga ccugcucagc uucuu 
               
               
                   
               
               
                 2465 
                 guccuaagac cugcucagcu ucuuc 
               
               
                   
               
               
                 2466 
                 uccuaagacc ugcucagcuu cuucc 
               
               
                   
               
               
                 2467 
                 ccuaagaccu gcucagcuuc uuccu 
               
               
                   
               
               
                 2468 
                 cuaagaccug cucagcuucu uccuu 
               
               
                   
               
               
                 2469 
                 uaagaccugc ucagcuucuu ccuua 
               
               
                   
               
               
                 2470 
                 aagaccugcu cagcuucuuc cuuag 
               
               
                   
               
               
                 2471 
                 agaccugcuc agcuucuucc uuagc 
               
               
                   
               
               
                 2472 
                 gaccugcuca gcuucuuccu uagcu 
               
               
                   
               
               
                 2473 
                 accugcucag cuucuuccuu agcuu 
               
               
                   
               
               
                 2474 
                 ccugcucagc uucuuccuua gcuuc 
               
               
                   
               
               
                 2475 
                 cugcucagcu ucuuccuuag cuucc 
               
               
                   
               
               
                 2476 
                 ugcucagcuu cuuccuuagc uucca 
               
               
                   
               
               
                 2477 
                 gcucagcuuc uuccuuagcu uccag 
               
               
                   
               
               
                 2478 
                 cucagcuucu uccuuagcuu ccagc 
               
               
                   
               
               
                 2479 
                 ucagcuucuu ccuuagcuuc cagcc 
               
               
                   
               
               
                 2480 
                 cagcuucuuc cuuagcuucc agcca 
               
               
                   
               
               
                 2481 
                 agcuucuucc uuagcuucca gccau 
               
               
                   
               
               
                 2482 
                 gcuucuuccu uagcuuccag ccauu 
               
               
                   
               
               
                 2483 
                 cuucuuccuu agcuuccagc cauug 
               
               
                   
               
               
                 2484 
                 uucuuccuua gcuuccagcc auugu 
               
               
                   
               
               
                 2485 
                 ucuuccuuag cuuccagcca uugug 
               
               
                   
               
               
                 2486 
                 cuuccuuagc uuccagccau ugugu 
               
               
                   
               
               
                 2487 
                 uuccuuagcu uccagccauu guguu 
               
               
                   
               
               
                 2488 
                 uccuuagcuu ccagccauug uguug 
               
               
                   
               
               
                 2489 
                 ccuuagcuuc cagccauugu guuga 
               
               
                   
               
               
                 2490 
                 cuuagcuucc agccauugug uugaa 
               
               
                   
               
               
                 2491 
                 uuagcuucca gccauugugu ugaau 
               
               
                   
               
               
                 2492 
                 uagcuuccag ccauuguguu gaauc 
               
               
                   
               
               
                 2493 
                 agcuuccagc cauuguguug aaucc 
               
               
                   
               
               
                 2494 
                 gcuuccagcc auuguguuga auccu 
               
               
                   
               
               
                 2495 
                 cuuccagcca uuguguugaa uccuu 
               
               
                   
               
               
                 2496 
                 uuccagccau uguguugaau ccuuu 
               
               
                   
               
               
                 2497 
                 uccagccauu guguugaauc cuuua 
               
               
                   
               
               
                 2498 
                 ccagccauug uguugaaucc uuuaa 
               
               
                   
               
               
                 2499 
                 cagccauugu guugaauccu uuaac 
               
               
                   
               
               
                 2500 
                 agccauugug uugaauccuu uaaca 
               
               
                   
               
               
                 2501 
                 gccauugugu ugaauccuuu aacau 
               
               
                   
               
               
                 2502 
                 ccauuguguu gaauccuuua acauu 
               
               
                   
               
               
                 2503 
                 cauuguguug aauccuuuaa cauuu 
               
               
                   
               
               
                 2504 
                 cauuuuugac cuacaugugg 
               
               
                   
               
               
                 2505 
                 uuugaccuac auguggaaag 
               
               
                   
               
               
                 2506 
                 uacauuuuug accuacaugu ggaaag 
               
               
                   
               
               
                 2507 
                 ggucuccuua ccuauga 
               
               
                   
               
               
                 2508 
                 ucuuaccuau gacuauggau gaga 
               
               
                   
               
               
                 2509 
                 auuuuugacc uacaugggaa ag 
               
               
                   
               
               
                 2510 
                 uacgaguuga uugucggacc cag 
               
               
                   
               
               
                 2511 
                 guggucuccu uaccuaugac ugugg 
               
               
                   
               
               
                 2512 
                 ugucucagua aucuucuuac cuau 
               
               
                   
               
               
                 2513 
                 ugcauguucc agucguugug ugg 
               
               
                   
               
               
                 2514 
                 cacuauucca gucaaauagg ucugg 
               
               
                   
               
               
                 2515 
                 auuuaccaac cuucaggauc gagua 
               
               
                   
               
               
                 2516 
                 ggccuaaaac acauacacau a 
               
               
                   
               
               
                 2517 
                 cccugaggca uucccaucuu gaau 
               
               
                   
               
               
                 2518 
                 aggacuuacu ugcuuuguuu 
               
               
                   
               
               
                 2519 
                 cuugaauuua ggagauucau cug 
               
               
                   
               
               
                 2520 
                 caucuucuga uaauuuuccu guu 
               
               
                   
               
               
                 2521 
                 ccauuacagu ugucuguguu 
               
               
                   
               
               
                 2522 
                 ugacagccug ugaaaucugu gag 
               
               
                   
               
               
                 2523 
                 uaaucugccu cuucuuuugg 
               
               
                   
               
               
                 2524 
                 cagcaguagu ugucaucugc 
               
               
                   
               
               
                 2525 
                 gccugagcug aucugcuggc aucuugc 
               
               
                   
               
               
                 2526 
                 gccugagcug aucugcuggc aucuugcagu u 
               
               
                   
               
               
                 2527 
                 ucugcuggca ucuugc 
               
               
                   
               
               
                 2528 
                 gccgguugac uucauccugu gc 
               
               
                   
               
               
                 2529 
                 gucugcaucc aggaacaugg guc 
               
               
                   
               
               
                 2530 
                 uacuuacugu cuguagcucu uucu 
               
               
                   
               
               
                 2531 
                 cugcauccag gaacaugggu cc 
               
               
                   
               
               
                 2532 
                 guugaagauc ugauagccgg uuga 
               
               
                   
               
               
                 2533 
                 ucagcuucug uuagccacug 
               
               
                   
               
               
                 2534 
                 uucagcuucu guuagccacu 
               
               
                   
               
               
                 2535 
                 uucagcuucu guuagccacu g 
               
               
                   
               
               
                 2536 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 2537 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 2538 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 2539 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 2540 
                 ucagcuucug uuagccacug au 
               
               
                   
               
               
                 2541 
                 uucagcuucu guuagccacu gau 
               
               
                   
               
               
                 2542 
                 ucagcuucug uuagccacug auu 
               
               
                   
               
               
                 2543 
                 uucagcuucu guuagccacu gauu 
               
               
                   
               
               
                 2544 
                 ucagcuucug uuagccacug auua 
               
               
                   
               
               
                 2545 
                 uucagcuucu guuagccacu gaua 
               
               
                   
               
               
                 2546 
                 ucagcuucug uuagccacug auuaa 
               
               
                   
               
               
                 2547 
                 uucagcuucu guuagccacu gauuaa 
               
               
                   
               
               
                 2548 
                 ucagcuucug uuagccacug auuaaa 
               
               
                   
               
               
                 2549 
                 uucagcuucu guuagccacu gauuaaa 
               
               
                   
               
               
                 2550 
                 cagcuucugu uagccacug 
               
               
                   
               
               
                 2551 
                 cagcuucugu uagccacuga u 
               
               
                   
               
               
                 2552 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 2553 
                 cagcuucugu uagccacuga uu 
               
               
                   
               
               
                 2554 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 2555 
                 cagcuucugu uagccacuga uua 
               
               
                   
               
               
                 2556 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 2557 
                 cagcuucugu uagccacuga uuaa 
               
               
                   
               
               
                 2558 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 2559 
                 cagcuucugu uagccacuga uuaaa 
               
               
                   
               
               
                 2560 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 2561 
                 agcuucuguu agccacugau 
               
               
                   
               
               
                 2562 
                 gcuucuguua gccacugauu 
               
               
                   
               
               
                 2563 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 2564 
                 gcuucuguua gccacugauu a 
               
               
                   
               
               
                 2565 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 2566 
                 gcuucuguua gccacugauu aa 
               
               
                   
               
               
                 2567 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 2568 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 2569 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 2570 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 2571 
                 ccauuuguau uuagcauguu ccc 
               
               
                   
               
               
                 2572 
                 agauaccauu uguauuuagc 
               
               
                   
               
               
                 2573 
                 gccauuucuc aacagaucu 
               
               
                   
               
               
                 2574 
                 gccauuucuc aacagaucug uca 
               
               
                   
               
               
                 2575 
                 auucucagga auuugugucu uuc 
               
               
                   
               
               
                 2576 
                 ucucaggaau uugugucuuu c 
               
               
                   
               
               
                 2577 
                 guucagcuuc uguuagcc 
               
               
                   
               
               
                 2578 
                 cugauuaaau aucuuuauau c 
               
               
                   
               
               
                 2579 
                 gccgccauuu cucaacag 
               
               
                   
               
               
                 2580 
                 gccgccauuu cucaacag 
               
               
                   
               
               
                 2581 
                 caggaauuug ugucuuuc 
               
               
                   
               
               
                 2582 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 2583 
                 auucaauguu cugacaacag uuugc 
               
               
                   
               
               
                 2584 
                 ccaguugcau ucaauguucu gacaa 
               
               
                   
               
               
                 2585 
                 caguugcauu caauguucug ac 
               
               
                   
               
               
                 2586 
                 aguugcauuc aauguucuga 
               
               
                   
               
               
                 2587 
                 gauugcugaa uuauuucuuc c 
               
               
                   
               
               
                 2588 
                 gauugcugaa uuauuucuuc cccag 
               
               
                   
               
               
                 2589 
                 auugcugaau uauuucuucc ccagu 
               
               
                   
               
               
                 2590 
                 uugcugaauu auuucuuccc caguu 
               
               
                   
               
               
                 2591 
                 ugcugaauua uuucuucccc aguug 
               
               
                   
               
               
                 2592 
                 gcugaauuau uucuucccca guugc 
               
               
                   
               
               
                 2593 
                 cugaauuauu ucuuccccag uugca 
               
               
                   
               
               
                 2594 
                 ugaauuauuu cuuccccagu ugcau 
               
               
                   
               
               
                 2595 
                 gaauuauuuc uuccccaguu gcauu 
               
               
                   
               
               
                 2596 
                 aauuauuucu uccccaguug cauuc 
               
               
                   
               
               
                 2597 
                 auuauuucuu ccccaguugc auuca 
               
               
                   
               
               
                 2598 
                 uuauuucuuc cccaguugca uucaa 
               
               
                   
               
               
                 2599 
                 uauuucuucc ccaguugcau ucaau 
               
               
                   
               
               
                 2600 
                 auuucuuccc caguugcauu caaug 
               
               
                   
               
               
                 2601 
                 uuucuucccc aguugcauuc aaugu 
               
               
                   
               
               
                 2602 
                 uucuucccca guugcauuca auguu 
               
               
                   
               
               
                 2603 
                 ucuuccccag uugcauucaa uguuc 
               
               
                   
               
               
                 2604 
                 cuuccccagu ugcauucaau guucu 
               
               
                   
               
               
                 2605 
                 uuccccaguu gcauucaaug uucug 
               
               
                   
               
               
                 2606 
                 uccccaguug cauucaaugu ucuga 
               
               
                   
               
               
                 2607 
                 ccccaguugc auucaauguu cugac 
               
               
                   
               
               
                 2608 
                 cccaguugca uucaauguuc ugaca 
               
               
                   
               
               
                 2609 
                 ccaguugcau ucaauguucu gacaa 
               
               
                   
               
               
                 2610 
                 caguugcauu caauguucug acaac 
               
               
                   
               
               
                 2611 
                 aguugcauuc aauguucuga caaca 
               
               
                   
               
               
                 2612 
                 uccuguagaa uacuggcauc 
               
               
                   
               
               
                 2613 
                 ugcagaccuc cugccaccgc agauuca 
               
               
                   
               
               
                 2614 
                 uugcagaccu ccugccaccg cagauucagg cuuc 
               
               
                   
               
               
                 2615 
                 guugcauuca auguucugac aacag 
               
               
                   
               
               
                 2616 
                 uugcauucaa uguucugaca acagu 
               
               
                   
               
               
                 2617 
                 ugcauucaau guucugacaa caguu 
               
               
                   
               
               
                 2618 
                 gcauucaaug uucugacaac aguuu 
               
               
                   
               
               
                 2619 
                 cauucaaugu ucugacaaca guuug 
               
               
                   
               
               
                 2620 
                 auucaauguu cugacaacag uuugc 
               
               
                   
               
               
                 2621 
                 ucaauguucu gacaacaguu ugccg 
               
               
                   
               
               
                 2622 
                 caauguucug acaacaguuu gccgc 
               
               
                   
               
               
                 2623 
                 aauguucuga caacaguuug ccgcu 
               
               
                   
               
               
                 2624 
                 auguucugac aacaguuugc cgcug 
               
               
                   
               
               
                 2625 
                 uguucugaca acaguuugcc gcugc 
               
               
                   
               
               
                 2626 
                 guucugacaa caguuugccg cugcc 
               
               
                   
               
               
                 2627 
                 uucugacaac aguuugccgc ugccc 
               
               
                   
               
               
                 2628 
                 ucugacaaca guuugccgcu gccca 
               
               
                   
               
               
                 2629 
                 cugacaacag uuugccgcug cccaa 
               
               
                   
               
               
                 2630 
                 ugacaacagu uugccgcugc ccaau 
               
               
                   
               
               
                 2631 
                 gacaacaguu ugccgcugcc caaug 
               
               
                   
               
               
                 2632 
                 acaacaguuu gccgcugccc aaugc 
               
               
                   
               
               
                 2633 
                 caacaguuug ccgcugccca augcc 
               
               
                   
               
               
                 2634 
                 aacaguuugc cgcugcccaa ugcca 
               
               
                   
               
               
                 2635 
                 acaguuugcc gcugcccaau gccau 
               
               
                   
               
               
                 2636 
                 caguuugccg cugcccaaug ccauc 
               
               
                   
               
               
                 2637 
                 aguuugccgc ugcccaaugc caucc 
               
               
                   
               
               
                 2638 
                 guuugccgcu gcccaaugcc auccu 
               
               
                   
               
               
                 2639 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 2640 
                 uugccgcugc ccaaugccau ccugg 
               
               
                   
               
               
                 2641 
                 ugccgcugcc caaugccauc cugga 
               
               
                   
               
               
                 2642 
                 gccgcugccc aaugccaucc uggag 
               
               
                   
               
               
                 2643 
                 ccgcugccca augccauccu ggagu 
               
               
                   
               
               
                 2644 
                 cgcugcccaa ugccauccug gaguu 
               
               
                   
               
               
                 2645 
                 uguuuuugag gauugcugaa 
               
               
                   
               
               
                 2646 
                 uguucugaca acaguuugcc gcugcccaau gccauccugg 
               
               
                   
               
               
                 2647 
                 cuguugcagu aaucuaugag 
               
               
                   
               
               
                 2648 
                 ugcaguaauc uaugaguuuc 
               
               
                   
               
               
                 2649 
                 gagucuucua ggagccuu 
               
               
                   
               
               
                 2650 
                 ugccauuguu ucaucagcuc uuu 
               
               
                   
               
               
                 2651 
                 uccuguagga cauuggcagu 
               
               
                   
               
               
                 2652 
                 cuuggagucu ucuaggagcc 
               
               
                   
               
               
                 2653 
                 uaggugccug ccggcuu 
               
               
                   
               
               
                 2654 
                 uucagcugua gccacacc 
               
               
                   
               
               
                 2655 
                 cugaacugcu ggaaagucgc c 
               
               
                   
               
               
                 2656 
                 cuggcuucca aaugggaccu gaaaaagaac 
               
               
                   
               
               
                 2657 
                 caauuuuucc cacucaguau u 
               
               
                   
               
               
                 2658 
                 uugaaguucc uggagucuu 
               
               
                   
               
               
                 2659 
                 uccucaggag gcagcucuaa au 
               
               
                   
               
               
                 2660 
                 uggcucucuc ccaggg 
               
               
                   
               
               
                 2661 
                 gagauggcuc ucucccaggg acccugg 
               
               
                   
               
               
                 2662 
                 gggcacuuug uuuggcg 
               
               
                   
               
               
                 2663 
                 ggucccagca aguuguuug 
               
               
                   
               
               
                 2664 
                 ugggaugguc ccagcaaguu guuug 
               
               
                   
               
               
                 2665 
                 guagagcucu gucauuuugg g 
               
               
                   
               
               
                 2666 
                 gcucaagaga uccacugcaa aaaac 
               
               
                   
               
               
                 2667 
                 gccauacgua cguaucauaa acauuc 
               
               
                   
               
               
                 2668 
                 ucugcaggau auccaugggc ugguc 
               
               
                   
               
               
                 2669 
                 gauccucccu guucgucccc uauuaug 
               
               
                   
               
               
                 2670 
                 ugcuuuagac uccuguaccu gaua 
               
               
                   
               
               
                 2671 
                 ggcggccuuu guguugac 
               
               
                   
               
               
                 2672 
                 ggacaggccu uuauguucgu gcugc 
               
               
                   
               
               
                 2673 
                 ccuuuauguu cgugcugcu 
               
               
                   
               
               
                 2674 
                 ccucagcucu ugaaguaaac gguuu 
               
               
                   
               
               
                 2675 
                 cucagcucuu gaaguaaacg guuua 
               
               
                   
               
               
                 2676 
                 ucagcucuug aaguaaacgg uuuac 
               
               
                   
               
               
                 2677 
                 cagcucuuga aguaaacggu uuacc 
               
               
                   
               
               
                 2678 
                 agcucuugaa guaaacgguu uaccg 
               
               
                   
               
               
                 2679 
                 gcucuugaag uaaacgguuu accgc 
               
               
                   
               
               
                 2680 
                 cucuugaagu aaacgguuua ccgcc 
               
               
                   
               
               
                 2681 
                 guaccuccaa caucaaggaa gaugg 
               
               
                   
               
               
                 2682 
                 uaccuccaac aucaaggaag auggc 
               
               
                   
               
               
                 2683 
                 accuccaaca ucaaggaaga uggca 
               
               
                   
               
               
                 2684 
                 ccuccaacau caaggaagau ggcau 
               
               
                   
               
               
                 2685 
                 cuccaacauc aaggaagaug gcauu 
               
               
                   
               
               
                 2686 
                 uccaacauca aggaagaugg cauuu 
               
               
                   
               
               
                 2687 
                 ccaacaucaa ggaagauggc auuuc 
               
               
                   
               
               
                 2688 
                 caacaucaag gaagauggca uuucu 
               
               
                   
               
               
                 2689 
                 aacaucaagg aagauggcau uucua 
               
               
                   
               
               
                 2690 
                 acaucaagga agauggcauu ucuag 
               
               
                   
               
               
                 2691 
                 caucaaggaa gauggcauuu cuagu 
               
               
                   
               
               
                 2692 
                 aucaaggaag auggcauuuc uaguu 
               
               
                   
               
               
                 2693 
                 ucaaggaaga uggcauuucu aguuu 
               
               
                   
               
               
                 2694 
                 caaggaagau ggcauuucua guuug 
               
               
                   
               
               
                 2695 
                 aaggaagaug gcauuucuag uuugg 
               
               
                   
               
               
                 2696 
                 aggaagaugg cauuucuagu uugga 
               
               
                   
               
               
                 2697 
                 ggaagauggc auuucuaguu uggag 
               
               
                   
               
               
                 2698 
                 gaagauggca uuucuaguuu ggaga 
               
               
                   
               
               
                 2699 
                 aagauggcau uucuaguuug gagau 
               
               
                   
               
               
                 2700 
                 agauggcauu ucuaguuugg agaug 
               
               
                   
               
               
                 2701 
                 gauggcauuu cuaguuugga gaugg 
               
               
                   
               
               
                 2702 
                 auggcauuuc uaguuuggag auggc 
               
               
                   
               
               
                 2703 
                 uggcauuucu aguuuggaga uggca 
               
               
                   
               
               
                 2704 
                 ggcauuucua guuuggagau ggcag 
               
               
                   
               
               
                 2705 
                 gcauuucuag uuuggagaug gcagu 
               
               
                   
               
               
                 2706 
                 cauuucuagu uuggagaugg caguu 
               
               
                   
               
               
                 2707 
                 auuucuaguu uggagauggc aguuu 
               
               
                   
               
               
                 2708 
                 uuucuaguuu ggagauggca guuuc 
               
               
                   
               
               
                 2709 
                 uucuaguuug gagauggcag uuucc 
               
               
                   
               
               
                 2710 
                 ucuaguuugg agauggcagu uuccu 
               
               
                   
               
               
                 2711 
                 cuaguuugga gauggcaguu uccuu 
               
               
                   
               
               
                 2712 
                 uaguuuggag auggcaguuu ccuua 
               
               
                   
               
               
                 2713 
                 aguuuggaga uggcaguuuc cuuag 
               
               
                   
               
               
                 2714 
                 guuuggagau ggcaguuucc uuagu 
               
               
                   
               
               
                 2715 
                 uuuggagaug gcaguuuccu uagua 
               
               
                   
               
               
                 2716 
                 uuggagaugg caguuuccuu aguaa 
               
               
                   
               
               
                 2717 
                 uggagauggc aguuuccuua guaac 
               
               
                   
               
               
                 2718 
                 gagauggcag uuuccuuagu aacca 
               
               
                   
               
               
                 2719 
                 agauggcagu uuccuuagua accac 
               
               
                   
               
               
                 2720 
                 gauggcaguu uccuuaguaa ccaca 
               
               
                   
               
               
                 2721 
                 auggcaguuu ccuuaguaac cacag 
               
               
                   
               
               
                 2722 
                 uggcaguuuc cuuaguaacc acagg 
               
               
                   
               
               
                 2723 
                 ggcaguuucc uuaguaacca caggu 
               
               
                   
               
               
                 2724 
                 gcaguuuccu uaguaaccac agguu 
               
               
                   
               
               
                 2725 
                 caguuuccuu aguaaccaca gguug 
               
               
                   
               
               
                 2726 
                 aguuuccuua guaaccacag guugu 
               
               
                   
               
               
                 2727 
                 guuuccuuag uaaccacagg uugug 
               
               
                   
               
               
                 2728 
                 uuuccuuagu aaccacaggu ugugu 
               
               
                   
               
               
                 2729 
                 uuccuuagua accacagguu guguc 
               
               
                   
               
               
                 2730 
                 uccuuaguaa ccacagguug uguca 
               
               
                   
               
               
                 2731 
                 ccuuaguaac cacagguugu gucac 
               
               
                   
               
               
                 2732 
                 cuuaguaacc acagguugug ucacc 
               
               
                   
               
               
                 2733 
                 uuaguaacca cagguugugu cacca 
               
               
                   
               
               
                 2734 
                 uaguaaccac agguuguguc accag 
               
               
                   
               
               
                 2735 
                 aguaaccaca gguuguguca ccaga 
               
               
                   
               
               
                 2736 
                 guaaccacag guugugucac cagag 
               
               
                   
               
               
                 2737 
                 uaaccacagg uugugucacc agagu 
               
               
                   
               
               
                 2738 
                 aaccacaggu ugugucacca gagua 
               
               
                   
               
               
                 2739 
                 accacagguu gugucaccag aguaa 
               
               
                   
               
               
                 2740 
                 ccacagguug ugucaccaga guaac 
               
               
                   
               
               
                 2741 
                 cacagguugu gucaccagag uaaca 
               
               
                   
               
               
                 2742 
                 acagguugug ucaccagagu aacag 
               
               
                   
               
               
                 2743 
                 cagguugugu caccagagua acagu 
               
               
                   
               
               
                 2744 
                 agguuguguc accagaguaa caguc 
               
               
                   
               
               
                 2745 
                 gguuguguca ccagaguaac agucu 
               
               
                   
               
               
                 2746 
                 guugugucac cagaguaaca gucug 
               
               
                   
               
               
                 2747 
                 uugugucacc agaguaacag ucuga 
               
               
                   
               
               
                 2748 
                 ugugucacca gaguaacagu cugag 
               
               
                   
               
               
                 2749 
                 gugucaccag aguaacaguc ugagu 
               
               
                   
               
               
                 2750 
                 ugucaccaga guaacagucu gagua 
               
               
                   
               
               
                 2751 
                 gucaccagag uaacagucug aguag 
               
               
                   
               
               
                 2752 
                 ucaccagagu aacagucuga guagg 
               
               
                   
               
               
                 2753 
                 caccagagua acagucugag uagga 
               
               
                   
               
               
                 2754 
                 accagaguaa cagucugagu aggag 
               
               
                   
               
               
                 2755 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 2756 
                 auucaauguu cugacaacag uuugc 
               
               
                   
               
               
                 2757 
                 ccaguugcau ucaauguucu gacaa 
               
               
                   
               
               
                 2758 
                 caguugcauu caauguucug ac 
               
               
                   
               
               
                 2759 
                 aguugcauuc aauguucuga 
               
               
                   
               
               
                 2760 
                 gauugcugaa uuauuucuuc c 
               
               
                   
               
               
                 2761 
                 gauugcugaa uuauuucuuc cccag 
               
               
                   
               
               
                 2762 
                 auugcugaau uauuucuucc ccagu 
               
               
                   
               
               
                 2763 
                 uugcugaauu auuucuuccc caguu 
               
               
                   
               
               
                 2764 
                 ugcugaauua uuucuucccc aguug 
               
               
                   
               
               
                 2765 
                 gcugaauuau uucuucccca guugc 
               
               
                   
               
               
                 2766 
                 cugaauuauu ucuuccccag uugca 
               
               
                   
               
               
                 2767 
                 ugaauuauuu cuuccccagu ugcau 
               
               
                   
               
               
                 2768 
                 gaauuauuuc uuccccaguu gcauu 
               
               
                   
               
               
                 2769 
                 aauuauuucu uccccaguug cauuc 
               
               
                   
               
               
                 2770 
                 auuauuucuu ccccaguugc auuca 
               
               
                   
               
               
                 2771 
                 uuauuucuuc cccaguugca uucaa 
               
               
                   
               
               
                 2772 
                 uauuucuucc ccaguugcau ucaau 
               
               
                   
               
               
                 2773 
                 auuucuuccc caguugcauu caaug 
               
               
                   
               
               
                 2774 
                 uuucuucccc aguugcauuc aaugu 
               
               
                   
               
               
                 2775 
                 uucuucccca guugcauuca auguu 
               
               
                   
               
               
                 2776 
                 ucuuccccag uugcauucaa uguuc 
               
               
                   
               
               
                 2777 
                 cuuccccagu ugcauucaau guucu 
               
               
                   
               
               
                 2778 
                 uuccccaguu gcauucaaug uucug 
               
               
                   
               
               
                 2779 
                 uccccaguug cauucaaugu ucuga 
               
               
                   
               
               
                 2780 
                 ccccaguugc auucaauguu cugac 
               
               
                   
               
               
                 2781 
                 cccaguugca uucaauguuc ugaca 
               
               
                   
               
               
                 2782 
                 ccaguugcau ucaauguucu gacaa 
               
               
                   
               
               
                 2783 
                 caguugcauu caauguucug acaac 
               
               
                   
               
               
                 2784 
                 aguugcauuc aauguucuga caaca 
               
               
                   
               
               
                 2785 
                 uccuguagaa uacuggcauc 
               
               
                   
               
               
                 2786 
                 ugcagaccuc cugccaccgc agauuca 
               
               
                   
               
               
                 2787 
                 uugcagaccu ccugccaccg cagauucagg cuuc 
               
               
                   
               
               
                 2788 
                 guugcauuca auguucugac aacag 
               
               
                   
               
               
                 2789 
                 uugcauucaa uguucugaca acagu 
               
               
                   
               
               
                 2790 
                 ugcauucaau guucugacaa caguu 
               
               
                   
               
               
                 2791 
                 gcauucaaug uucugacaac aguuu 
               
               
                   
               
               
                 2792 
                 cauucaaugu ucugacaaca guuug 
               
               
                   
               
               
                 2793 
                 auucaauguu cugacaacag uuugc 
               
               
                   
               
               
                 2794 
                 ucaauguucu gacaacaguu ugccg 
               
               
                   
               
               
                 2795 
                 caauguucug acaacaguuu gccgc 
               
               
                   
               
               
                 2796 
                 aauguucuga caacaguuug ccgcu 
               
               
                   
               
               
                 2797 
                 auguucugac aacaguuugc cgcug 
               
               
                   
               
               
                 2798 
                 uguucugaca acaguuugcc gcugc 
               
               
                   
               
               
                 2799 
                 guucugacaa caguuugccg cugcc 
               
               
                   
               
               
                 2800 
                 uucugacaac aguuugccgc ugccc 
               
               
                   
               
               
                 2801 
                 ucugacaaca guuugccgcu gccca 
               
               
                   
               
               
                 2802 
                 cugacaacag uuugccgcug cccaa 
               
               
                   
               
               
                 2803 
                 ugacaacagu uugccgcugc ccaau 
               
               
                   
               
               
                 2804 
                 gacaacaguu ugccgcugcc caaug 
               
               
                   
               
               
                 2805 
                 acaacaguuu gccgcugccc aaugc 
               
               
                   
               
               
                 2806 
                 caacaguuug ccgcugccca augcc 
               
               
                   
               
               
                 2807 
                 aacaguuugc cgcugcccaa ugcca 
               
               
                   
               
               
                 2808 
                 acaguuugcc gcugcccaau gccau 
               
               
                   
               
               
                 2809 
                 caguuugccg cugcccaaug ccauc 
               
               
                   
               
               
                 2810 
                 aguuugccgc ugcccaaugc caucc 
               
               
                   
               
               
                 2811 
                 guuugccgcu gcccaaugcc auccu 
               
               
                   
               
               
                 2812 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 2813 
                 uugccgcugc ccaaugccau ccugg 
               
               
                   
               
               
                 2814 
                 ugccgcugcc caaugccauc cugga 
               
               
                   
               
               
                 2815 
                 gccgcugccc aaugccaucc uggag 
               
               
                   
               
               
                 2816 
                 ccgcugccca augccauccu ggagu 
               
               
                   
               
               
                 2817 
                 cgcugcccaa ugccauccug gaguu 
               
               
                   
               
               
                 2818 
                 uguuuuugag gauugcugaa 
               
               
                   
               
               
                 2819 
                 uguucugaca acaguuugcc gcugcccaau gccauccugg 
               
               
                   
               
               
                 2820 
                 cucuggccug uccuaagacc ugcuc 
               
               
                   
               
               
                 2821 
                 ucuggccugu ccuaagaccu gcuca 
               
               
                   
               
               
                 2822 
                 cuggccuguc cuaagaccug cucag 
               
               
                   
               
               
                 2823 
                 uggccugucc uaagaccugc ucagc 
               
               
                   
               
               
                 2824 
                 ggccuguccu aagaccugcu cagcu 
               
               
                   
               
               
                 2825 
                 gccuguccua agaccugcuc agcuu 
               
               
                   
               
               
                 2826 
                 ccuguccuaa gaccugcuca gcuuc 
               
               
                   
               
               
                 2827 
                 cuguccuaag accugcucag cuucu 
               
               
                   
               
               
                 2828 
                 uguccuaaga ccugcucagc uucuu 
               
               
                   
               
               
                 2829 
                 guccuaagac cugcucagcu ucuuc 
               
               
                   
               
               
                 2830 
                 uccuaagacc ugcucagcuu cuucc 
               
               
                   
               
               
                 2831 
                 ccuaagaccu gcucagcuuc uuccu 
               
               
                   
               
               
                 2832 
                 cuaagaccug cucagcuucu uccuu 
               
               
                   
               
               
                 2833 
                 uaagaccugc ucagcuucuu ccuua 
               
               
                   
               
               
                 2834 
                 aagaccugcu cagcuucuuc cuuag 
               
               
                   
               
               
                 2835 
                 agaccugcuc agcuucuucc uuagc 
               
               
                   
               
               
                 2836 
                 gaccugcuca gcuucuuccu uagcu 
               
               
                   
               
               
                 2837 
                 accugcucag cuucuuccuu agcuu 
               
               
                   
               
               
                 2838 
                 ccugcucagc uucuuccuua gcuuc 
               
               
                   
               
               
                 2839 
                 cugcucagcu ucuuccuuag cuucc 
               
               
                   
               
               
                 2840 
                 ugcucagcuu cuuccuuagc uucca 
               
               
                   
               
               
                 2841 
                 gcucagcuuc uuccuuagcu uccag 
               
               
                   
               
               
                 2842 
                 cucagcuucu uccuuagcuu ccagc 
               
               
                   
               
               
                 2843 
                 ucagcuucuu ccuuagcuuc cagcc 
               
               
                   
               
               
                 2844 
                 cagcuucuuc cuuagcuucc agcca 
               
               
                   
               
               
                 2845 
                 agcuucuucc uuagcuucca gccau 
               
               
                   
               
               
                 2846 
                 gcuucuuccu uagcuuccag ccauu 
               
               
                   
               
               
                 2847 
                 cuucuuccuu agcuuccagc cauug 
               
               
                   
               
               
                 2848 
                 uucuuccuua gcuuccagcc auugu 
               
               
                   
               
               
                 2849 
                 ucuuccuuag cuuccagcca uugug 
               
               
                   
               
               
                 2850 
                 cuuccuuagc uuccagccau ugugu 
               
               
                   
               
               
                 2851 
                 uuccuuagcu uccagccauu guguu 
               
               
                   
               
               
                 2852 
                 uccuuagcuu ccagccauug uguug 
               
               
                   
               
               
                 2853 
                 ccuuagcuuc cagccauugu guuga 
               
               
                   
               
               
                 2854 
                 cuuagcuucc agccauugug uugaa 
               
               
                   
               
               
                 2855 
                 uuagcuucca gccauugugu ugaau 
               
               
                   
               
               
                 2856 
                 uagcuuccag ccauuguguu gaauc 
               
               
                   
               
               
                 2857 
                 agcuuccagc cauuguguug aaucc 
               
               
                   
               
               
                 2858 
                 gcuuccagcc auuguguuga auccu 
               
               
                   
               
               
                 2859 
                 cuuccagcca uuguguugaa uccuu 
               
               
                   
               
               
                 2860 
                 uuccagccau uguguugaau ccuuu 
               
               
                   
               
               
                 2861 
                 uccagccauu guguugaauc cuuua 
               
               
                   
               
               
                 2862 
                 ccagccauug uguugaaucc uuuaa 
               
               
                   
               
               
                 2863 
                 cagccauugu guugaauccu uuaac 
               
               
                   
               
               
                 2864 
                 agccauugug uugaauccuu uaaca 
               
               
                   
               
               
                 2865 
                 gccauugugu ugaauccuuu aacau 
               
               
                   
               
               
                 2866 
                 ccauuguguu gaauccuuua acauu 
               
               
                   
               
               
                 2867 
                 cauuguguug aauccuuuaa cauuu 
               
               
                   
               
               
                 2868 
                 ucagcuucug uuagccacug 
               
               
                   
               
               
                 2869 
                 uucagcuucu guuagccacu 
               
               
                   
               
               
                 2870 
                 uucagcuucu guuagccacu g 
               
               
                   
               
               
                 2871 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 2872 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 2873 
                 ucagcuucug uuagccacug a 
               
               
                   
               
               
                 2874 
                 uucagcuucu guuagccacu ga 
               
               
                   
               
               
                 2875 
                 ucagcuucug uuagccacug au 
               
               
                   
               
               
                 2876 
                 uucagcuucu guuagccacu gau 
               
               
                   
               
               
                 2877 
                 ucagcuucug uuagccacug auu 
               
               
                   
               
               
                 2878 
                 uucagcuucu guuagccacu gauu 
               
               
                   
               
               
                 2879 
                 ucagcuucug uuagccacug auua 
               
               
                   
               
               
                 2880 
                 uucagcuucu guuagccacu gaua 
               
               
                   
               
               
                 2881 
                 ucagcuucug uuagccacug auuaa 
               
               
                   
               
               
                 2882 
                 uucagcuucu guuagccacu gauuaa 
               
               
                   
               
               
                 2883 
                 ucagcuucug uuagccacug auuaaa 
               
               
                   
               
               
                 2884 
                 uucagcuucu guuagccacu gauuaaa 
               
               
                   
               
               
                 2885 
                 cagcuucugu uagccacug 
               
               
                   
               
               
                 2886 
                 cagcuucugu uagccacuga u 
               
               
                   
               
               
                 2887 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 2888 
                 cagcuucugu uagccacuga uu 
               
               
                   
               
               
                 2889 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 2890 
                 cagcuucugu uagccacuga uua 
               
               
                   
               
               
                 2891 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 2892 
                 cagcuucugu uagccacuga uuaa 
               
               
                   
               
               
                 2893 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 2894 
                 cagcuucugu uagccacuga uuaaa 
               
               
                   
               
               
                 2895 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 2896 
                 agcuucuguu agccacugau 
               
               
                   
               
               
                 2897 
                 gcuucuguua gccacugauu 
               
               
                   
               
               
                 2898 
                 agcuucuguu agccacugau u 
               
               
                   
               
               
                 2899 
                 gcuucuguua gccacugauu a 
               
               
                   
               
               
                 2900 
                 agcuucuguu agccacugau ua 
               
               
                   
               
               
                 2901 
                 gcuucuguua gccacugauu aa 
               
               
                   
               
               
                 2902 
                 agcuucuguu agccacugau uaa 
               
               
                   
               
               
                 2903 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 2904 
                 agcuucuguu agccacugau uaaa 
               
               
                   
               
               
                 2905 
                 gcuucuguua gccacugauu aaa 
               
               
                   
               
               
                 2906 
                 ccauuuguau uuagcauguu ccc 
               
               
                   
               
               
                 2907 
                 agauaccauu uguauuuagc 
               
               
                   
               
               
                 2908 
                 gccauuucuc aacagaucu 
               
               
                   
               
               
                 2909 
                 gccauuucuc aacagaucug uca 
               
               
                   
               
               
                 2910 
                 auucucagga auuugugucu uuc 
               
               
                   
               
               
                 2911 
                 ucucaggaau uugugucuuu c 
               
               
                   
               
               
                 2912 
                 guucagcuuc uguuagcc 
               
               
                   
               
               
                 2913 
                 cugauuaaau aucuuuauau c 
               
               
                   
               
               
                 2914 
                 gccgccauuu cucaacag 
               
               
                   
               
               
                 2915 
                 guauuuagca uguuccca 
               
               
                   
               
               
                 2916 
                 caggaauuug ugucuuuc 
               
               
                   
               
               
                 2917 
                 gcuuuucuuu uaguugcugc ucuuu 
               
               
                   
               
               
                 2918 
                 cuuuucuuuu aguugcugcu cuuuu 
               
               
                   
               
               
                 2919 
                 uuuucuuuua guugcugcuc uuuuc 
               
               
                   
               
               
                 2920 
                 uuucuuuuag uugcugcucu uuucc 
               
               
                   
               
               
                 2921 
                 uucuuuuagu ugcugcucuu uucca 
               
               
                   
               
               
                 2922 
                 ucuuuuaguu gcugcucuuu uccag 
               
               
                   
               
               
                 2923 
                 cuuuuaguug cugcucuuuu ccagg 
               
               
                   
               
               
                 2924 
                 uuuuaguugc ugcucuuuuc caggu 
               
               
                   
               
               
                 2925 
                 uuuaguugcu gcucuuuucc agguu 
               
               
                   
               
               
                 2926 
                 uuaguugcug cucuuuucca gguuc 
               
               
                   
               
               
                 2927 
                 uaguugcugc ucuuuuccag guuca 
               
               
                   
               
               
                 2928 
                 aguugcugcu cuuuuccagg uucaa 
               
               
                   
               
               
                 2929 
                 guugcugcuc uuuuccaggu ucaag 
               
               
                   
               
               
                 2930 
                 uugcugcucu uuuccagguu caagu 
               
               
                   
               
               
                 2931 
                 ugcugcucuu uuccagguuc aagug 
               
               
                   
               
               
                 2932 
                 gcugcucuuu uccagguuca agugg 
               
               
                   
               
               
                 2933 
                 cugcucuuuu ccagguucaa guggg 
               
               
                   
               
               
                 2934 
                 ugcucuuuuc cagguucaag uggga 
               
               
                   
               
               
                 2935 
                 gcucuuuucc agguucaagu gggac 
               
               
                   
               
               
                 2936 
                 cucuuuucca gguucaagug ggaua 
               
               
                   
               
               
                 2937 
                 ucuuuuccag guucaagugg gauac 
               
               
                   
               
               
                 2938 
                 ucuuuuccag guucaagugg 
               
               
                   
               
               
                 2939 
                 cuuuuccagg uucaaguggg auacu 
               
               
                   
               
               
                 2940 
                 uuuuccaggu ucaaguggga uacua 
               
               
                   
               
               
                 2941 
                 uuuccagguu caagugggau acuag 
               
               
                   
               
               
                 2942 
                 uuccagguuc aagugggaua cuagc 
               
               
                   
               
               
                 2943 
                 uccagguuca agugggauac uagca 
               
               
                   
               
               
                 2944 
                 ccagguucaa gugggauacu agcaa 
               
               
                   
               
               
                 2945 
                 cagguucaag ugggauacua gcaau 
               
               
                   
               
               
                 2946 
                 agguucaagu gggauacuag caaug 
               
               
                   
               
               
                 2947 
                 gguucaagug ggauacuagc aaugu 
               
               
                   
               
               
                 2948 
                 guucaagugg gauacuagca auguu 
               
               
                   
               
               
                 2949 
                 uucaaguggg auacuagcaa uguua 
               
               
                   
               
               
                 2950 
                 ucaaguggga uacuagcaau guuau 
               
               
                   
               
               
                 2951 
                 caagugggau acuagcaaug uuauc 
               
               
                   
               
               
                 2952 
                 aagugggaua cuagcaaugu uaucu 
               
               
                   
               
               
                 2953 
                 agugggauac uagcaauguu aucug 
               
               
                   
               
               
                 2954 
                 gugggauacu agcaauguua ucugc 
               
               
                   
               
               
                 2955 
                 ugggauacua gcaauguuau cugcu 
               
               
                   
               
               
                 2956 
                 gggauacuag caauguuauc ugcuu 
               
               
                   
               
               
                 2957 
                 ggauacuagc aauguuaucu gcuuc 
               
               
                   
               
               
                 2958 
                 gauacuagca auguuaucug cuucc 
               
               
                   
               
               
                 2959 
                 auacuagcaa uguuaucugc uuccu 
               
               
                   
               
               
                 2960 
                 uacuagcaau guuaucugcu uccuc 
               
               
                   
               
               
                 2961 
                 acuagcaaug uuaucugcuu ccucc 
               
               
                   
               
               
                 2962 
                 cuagcaaugu uaucugcuuc cucca 
               
               
                   
               
               
                 2963 
                 uagcaauguu aucugcuucc uccaa 
               
               
                   
               
               
                 2964 
                 agcaauguua ucugcuuccu ccaac 
               
               
                   
               
               
                 2965 
                 gcaauguuau cugcuuccuc caacc 
               
               
                   
               
               
                 2966 
                 caauguuauc ugcuuccucc aacca 
               
               
                   
               
               
                 2967 
                 aauguuaucu gcuuccucca accau 
               
               
                   
               
               
                 2968 
                 auguuaucug cuuccuccaa ccaua 
               
               
                   
               
               
                 2969 
                 uguuaucugc uuccuccaac cauaa 
               
               
                   
               
               
                 2970 
                 agccucuuga uugcuggucu uguuu 
               
               
                   
               
               
                 2971 
                 gccucuugau ugcuggucuu guuuu 
               
               
                   
               
               
                 2972 
                 ccucuugauu gcuggucuug uuuuu 
               
               
                   
               
               
                 2973 
                 ccucuugauu gcuggucuug 
               
               
                   
               
               
                 2974 
                 cucuugauug cuggucuugu uuuuc 
               
               
                   
               
               
                 2975 
                 ucuugauugc uggucuuguu uuuca 
               
               
                   
               
               
                 2976 
                 cuugauugcu ggucuuguuu uucaa 
               
               
                   
               
               
                 2977 
                 uugauugcug gucuuguuuu ucaaa 
               
               
                   
               
               
                 2978 
                 ugauugcugg ucuuguuuuu caaau 
               
               
                   
               
               
                 2979 
                 gauugcuggu cuuguuuuuc aaauu 
               
               
                   
               
               
                 2980 
                 gauugcuggu cuuguuuuuc 
               
               
                   
               
               
                 2981 
                 auugcugguc uuguuuuuca aauuu 
               
               
                   
               
               
                 2982 
                 uugcuggucu uguuuuucaa auuuu 
               
               
                   
               
               
                 2983 
                 ugcuggucuu guuuuucaaa uuuug 
               
               
                   
               
               
                 2984 
                 gcuggucuug uuuuucaaau uuugg 
               
               
                   
               
               
                 2985 
                 cuggucuugu uuuucaaauu uuggg 
               
               
                   
               
               
                 2986 
                 uggucuuguu uuucaaauuu ugggc 
               
               
                   
               
               
                 2987 
                 ggucuuguuu uucaaauuuu gggca 
               
               
                   
               
               
                 2988 
                 gucuuguuuu ucaaauuuug ggcag 
               
               
                   
               
               
                 2989 
                 ucuuguuuuu caaauuuugg gcagc 
               
               
                   
               
               
                 2990 
                 cuuguuuuuc aaauuuuggg cagcg 
               
               
                   
               
               
                 2991 
                 uuguuuuuca aauuuugggc agcgg 
               
               
                   
               
               
                 2992 
                 uguuuuucaa auuuugggca gcggu 
               
               
                   
               
               
                 2993 
                 guuuuucaaa uuuugggcag cggua 
               
               
                   
               
               
                 2994 
                 uuuuucaaau uuugggcagc gguaa 
               
               
                   
               
               
                 2995 
                 uuuucaaauu uugggcagcg guaau 
               
               
                   
               
               
                 2996 
                 uuucaaauuu ugggcagcgg uaaug 
               
               
                   
               
               
                 2997 
                 uucaaauuuu gggcagcggu aauga 
               
               
                   
               
               
                 2998 
                 ucaaauuuug ggcagcggua augag 
               
               
                   
               
               
                 2999 
                 caaauuuugg gcagcgguaa ugagu 
               
               
                   
               
               
                 3000 
                 aaauuuuggg cagcgguaau gaguu 
               
               
                   
               
               
                 3001 
                 aauuuugggc agcgguaaug aguuc 
               
               
                   
               
               
                 3002 
                 auuuugggca gcgguaauga guucu 
               
               
                   
               
               
                 3003 
                 uuuugggcag cgguaaugag uucuu 
               
               
                   
               
               
                 3004 
                 uuugggcagc gguaaugagu ucuuc 
               
               
                   
               
               
                 3005 
                 uugggcagcg guaaugaguu cuucc 
               
               
                   
               
               
                 3006 
                 ugggcagcgg uaaugaguuc uucca 
               
               
                   
               
               
                 3007 
                 gggcagcggu aaugaguucu uccaa 
               
               
                   
               
               
                 3008 
                 ggcagcggua augaguucuu ccaac 
               
               
                   
               
               
                 3009 
                 gcagcgguaa ugaguucuuc caacu 
               
               
                   
               
               
                 3010 
                 cagcgguaau gaguucuucc aacug 
               
               
                   
               
               
                 3011 
                 agcgguaaug aguucuucca acugg 
               
               
                   
               
               
                 3012 
                 gcgguaauga guucuuccaa cuggg 
               
               
                   
               
               
                 3013 
                 cgguaaugag uucuuccaac ugggg 
               
               
                   
               
               
                 3014 
                 gguaaugagu ucuuccaacu gggga 
               
               
                   
               
               
                 3015 
                 gguaaugagu ucuuccaacu gg 
               
               
                   
               
               
                 3016 
                 guaaugaguu cuuccaacug gggac 
               
               
                   
               
               
                 3017 
                 uaaugaguuc uuccaacugg ggacg 
               
               
                   
               
               
                 3018 
                 aaugaguucu uccaacuggg gacgc 
               
               
                   
               
               
                 3019 
                 augaguucuu ccaacugggg acgcc 
               
               
                   
               
               
                 3020 
                 ugaguucuuc caacugggga cgccu 
               
               
                   
               
               
                 3021 
                 gaguucuucc aacuggggac gccuc 
               
               
                   
               
               
                 3022 
                 aguucuucca acuggggacg ccucu 
               
               
                   
               
               
                 3023 
                 guucuuccaa cuggggacgc cucug 
               
               
                   
               
               
                 3024 
                 uucuuccaac uggggacgcc ucugu 
               
               
                   
               
               
                 3025 
                 ucuuccaacu ggggacgccu cuguu 
               
               
                   
               
               
                 3026 
                 cuuccaacug gggacgccuc uguuc 
               
               
                   
               
               
                 3027 
                 uuccaacugg ggacgccucu guucc 
               
               
                   
               
               
                 3028 
                 uccaacuggg gacgccucug uucca 
               
               
                   
               
               
                 3029 
                 ccaacugggg acgccucugu uccaa 
               
               
                   
               
               
                 3030 
                 caacugggga cgccucuguu ccaaa 
               
               
                   
               
               
                 3031 
                 aacuggggac gccucuguuc caaau 
               
               
                   
               
               
                 3032 
                 acuggggacg ccucuguucc aaauc 
               
               
                   
               
               
                 3033 
                 cuggggacgc cucuguucca aaucc 
               
               
                   
               
               
                 3034 
                 uggggacgcc ucuguuccaa auccu 
               
               
                   
               
               
                 3035 
                 ggggacgccu cuguuccaaa uccug 
               
               
                   
               
               
                 3036 
                 gggacgccuc uguuccaaau ccugc 
               
               
                   
               
               
                 3037 
                 ggacgccucu guuccaaauc cugca 
               
               
                   
               
               
                 3038 
                 gacgccucug uuccaaaucc ugcau 
               
               
                   
               
               
                 3039 
                 ccaauagugg ucaguccagg agcua 
               
               
                   
               
               
                 3040 
                 caauaguggu caguccagga gcuag 
               
               
                   
               
               
                 3041 
                 aauagugguc aguccaggag cuagg 
               
               
                   
               
               
                 3042 
                 auagugguca guccaggagc uaggu 
               
               
                   
               
               
                 3043 
                 auagugguca guccaggagc u 
               
               
                   
               
               
                 3044 
                 uaguggucag uccaggagcu agguc 
               
               
                   
               
               
                 3045 
                 aguggucagu ccaggagcua gguca 
               
               
                   
               
               
                 3046 
                 guggucaguc caggagcuag gucag 
               
               
                   
               
               
                 3047 
                 uggucagucc aggagcuagg ucagg 
               
               
                   
               
               
                 3048 
                 ggucagucca ggagcuaggu caggc 
               
               
                   
               
               
                 3049 
                 gucaguccag gagcuagguc aggcu 
               
               
                   
               
               
                 3050 
                 ucaguccagg agcuagguca ggcug 
               
               
                   
               
               
                 3051 
                 caguccagga gcuaggucag gcugc 
               
               
                   
               
               
                 3052 
                 aguccaggag cuaggucagg cugcu 
               
               
                   
               
               
                 3053 
                 guccaggagc uaggucaggc ugcuu 
               
               
                   
               
               
                 3054 
                 uccaggagcu aggucaggcu gcuuu 
               
               
                   
               
               
                 3055 
                 ccaggagcua ggucaggcug cuuug 
               
               
                   
               
               
                 3056 
                 caggagcuag gucaggcugc uuugc 
               
               
                   
               
               
                 3057 
                 aggagcuagg ucaggcugcu uugcc 
               
               
                   
               
               
                 3058 
                 ggagcuaggu caggcugcuu ugccc 
               
               
                   
               
               
                 3059 
                 gagcuagguc aggcugcuuu gcccu 
               
               
                   
               
               
                 3060 
                 agcuagguca ggcugcuuug cccuc 
               
               
                   
               
               
                 3061 
                 gcuaggucag gcugcuuugc ccuca 
               
               
                   
               
               
                 3062 
                 cucagcucuu gaaguaaacg guuua 
               
               
                   
               
               
                 3063 
                 cagcucuuga aguaaacggu uuacc 
               
               
                   
               
               
                 3064 
                 gcucuugaag uaaacgguuu accgc 
               
               
                   
               
               
                 3065 
                 cuaggucagg cugcuuugcc cucag 
               
               
                   
               
               
                 3066 
                 uaggucaggc ugcuuugccc ucagc 
               
               
                   
               
               
                 3067 
                 aggucaggcu gcuuugcccu cagcu 
               
               
                   
               
               
                 3068 
                 ggucaggcug cuuugcccuc agcuc 
               
               
                   
               
               
                 3069 
                 gucaggcugc uuugcccuca gcucu 
               
               
                   
               
               
                 3070 
                 ucaggcugcu uugcccucag cucuu 
               
               
                   
               
               
                 3071 
                 caggcugcuu ugcccucagc ucuug 
               
               
                   
               
               
                 3072 
                 aggcugcuuu gcccucagcu cuuga 
               
               
                   
               
               
                 3073 
                 ggcugcuuug cccucagcuc uugaa 
               
               
                   
               
               
                 3074 
                 gcugcuuugc ccucagcucu ugaag 
               
               
                   
               
               
                 3075 
                 cugcuuugcc cucagcucuu gaagu 
               
               
                   
               
               
                 3076 
                 ugcuuugccc ucagcucuug aagua 
               
               
                   
               
               
                 3077 
                 gcuuugcccu cagcucuuga aguaa 
               
               
                   
               
               
                 3078 
                 cuuugcccuc agcucuugaa guaaa 
               
               
                   
               
               
                 3079 
                 uuugcccuca gcucuugaag uaaac 
               
               
                   
               
               
                 3080 
                 uugcccucag cucuugaagu aaacg 
               
               
                   
               
               
                 3081 
                 ugcccucagc ucuugaagua aacgg 
               
               
                   
               
               
                 3082 
                 gcccucagcu cuugaaguaa acggu 
               
               
                   
               
               
                 3083 
                 cccucagcuc uugaaguaaa cgguu 
               
               
                   
               
               
                 3084 
                 ccucagcucu ugaaguaaac 
               
               
                   
               
               
                 3085 
                 ccucagcucu ugaaguaaac g 
               
               
                   
               
               
                 3086 
                 cucagcucuu gaaguaaacg 
               
               
                   
               
               
                 3087 
                 ccucagcucu ugaaguaaac gguuu 
               
               
                   
               
               
                 3088 
                 ucagcucuug aaguaaacgg uuuac 
               
               
                   
               
               
                 3089 
                 agcucuugaa guaaacgguu uaccg 
               
               
                   
               
               
                 3090 
                 cucuugaagu aaacgguuua ccgcc 
               
               
                   
               
               
                 3091 
                 ccacaggcgu ugcacuuugc aaugc 
               
               
                   
               
               
                 3092 
                 cacaggcguu gcacuuugca augcu 
               
               
                   
               
               
                 3093 
                 acaggcguug cacuuugcaa ugcug 
               
               
                   
               
               
                 3094 
                 caggcguugc acuuugcaau gcugc 
               
               
                   
               
               
                 3095 
                 aggcguugca cuuugcaaug cugcu 
               
               
                   
               
               
                 3096 
                 ggcguugcac uuugcaaugc ugcug 
               
               
                   
               
               
                 3097 
                 gcguugcacu uugcaaugcu gcugu 
               
               
                   
               
               
                 3098 
                 cguugcacuu ugcaaugcug cuguc 
               
               
                   
               
               
                 3099 
                 cguugcacuu ugcaaugcug cug 
               
               
                   
               
               
                 3100 
                 guugcacuuu gcaaugcugc ugucu 
               
               
                   
               
               
                 3101 
                 uugcacuuug caaugcugcu gucuu 
               
               
                   
               
               
                 3102 
                 ugcacuuugc aaugcugcug ucuuc 
               
               
                   
               
               
                 3103 
                 gcacuuugca augcugcugu cuucu 
               
               
                   
               
               
                 3104 
                 cacuuugcaa ugcugcuguc uucuu 
               
               
                   
               
               
                 3105 
                 acuuugcaau gcugcugucu ucuug 
               
               
                   
               
               
                 3106 
                 cuuugcaaug cugcugucuu cuugc 
               
               
                   
               
               
                 3107 
                 uuugcaaugc ugcugucuuc uugcu 
               
               
                   
               
               
                 3108 
                 uugcaaugcu gcugucuucu ugcua 
               
               
                   
               
               
                 3109 
                 ugcaaugcug cugucuucuu gcuau 
               
               
                   
               
               
                 3110 
                 gcaaugcugc ugucuucuug cuaug 
               
               
                   
               
               
                 3111 
                 caaugcugcu gucuucuugc uauga 
               
               
                   
               
               
                 3112 
                 aaugcugcug ucuucuugcu augaa 
               
               
                   
               
               
                 3113 
                 augcugcugu cuucuugcua ugaau 
               
               
                   
               
               
                 3114 
                 ugcugcuguc uucuugcuau gaaua 
               
               
                   
               
               
                 3115 
                 gcugcugucu ucuugcuaug aauaa 
               
               
                   
               
               
                 3116 
                 cugcugucuu cuugcuauga auaau 
               
               
                   
               
               
                 3117 
                 ugcugucuuc uugcuaugaa uaaug 
               
               
                   
               
               
                 3118 
                 gcugucuucu ugcuaugaau aaugu 
               
               
                   
               
               
                 3119 
                 cugucuucuu gcuaugaaua auguc 
               
               
                   
               
               
                 3120 
                 ugucuucuug cuaugaauaa uguca 
               
               
                   
               
               
                 3121 
                 gucuucuugc uaugaauaau gucaa 
               
               
                   
               
               
                 3122 
                 ucuucuugcu augaauaaug ucaau 
               
               
                   
               
               
                 3123 
                 cuucuugcua ugaauaaugu caauc 
               
               
                   
               
               
                 3124 
                 uucuugcuau gaauaauguc aaucc 
               
               
                   
               
               
                 3125 
                 ucuugcuaug aauaauguca auccg 
               
               
                   
               
               
                 3126 
                 cuugcuauga auaaugucaa uccga 
               
               
                   
               
               
                 3127 
                 uugcuaugaa uaaugucaau ccgac 
               
               
                   
               
               
                 3128 
                 ugcuaugaau aaugucaauc cgacc 
               
               
                   
               
               
                 3129 
                 gcuaugaaua augucaaucc gaccu 
               
               
                   
               
               
                 3130 
                 cuaugaauaa ugucaauccg accug 
               
               
                   
               
               
                 3131 
                 uaugaauaau gucaauccga ccuga 
               
               
                   
               
               
                 3132 
                 augaauaaug ucaauccgac cugag 
               
               
                   
               
               
                 3133 
                 ugaauaaugu caauccgacc ugagc 
               
               
                   
               
               
                 3134 
                 gaauaauguc aauccgaccu gagcu 
               
               
                   
               
               
                 3135 
                 aauaauguca auccgaccug agcuu 
               
               
                   
               
               
                 3136 
                 auaaugucaa uccgaccuga gcuuu 
               
               
                   
               
               
                 3137 
                 uaaugucaau ccgaccugag cuuug 
               
               
                   
               
               
                 3138 
                 aaugucaauc cgaccugagc uuugu 
               
               
                   
               
               
                 3139 
                 augucaaucc gaccugagcu uuguu 
               
               
                   
               
               
                 3140 
                 ugucaauccg accugagcuu uguug 
               
               
                   
               
               
                 3141 
                 gucaauccga ccugagcuuu guugu 
               
               
                   
               
               
                 3142 
                 ucaauccgac cugagcuuug uugua 
               
               
                   
               
               
                 3143 
                 caauccgacc ugagcuuugu uguag 
               
               
                   
               
               
                 3144 
                 aauccgaccu gagcuuuguu guaga 
               
               
                   
               
               
                 3145 
                 auccgaccug agcuuuguug uagac 
               
               
                   
               
               
                 3146 
                 uccgaccuga gcuuuguugu agacu 
               
               
                   
               
               
                 3147 
                 ccgaccugag cuuuguugua gacua 
               
               
                   
               
               
                 3148 
                 cgaccugagc uuuguuguag 
               
               
                   
               
               
                 3149 
                 cgaccugagc uuuguuguag acuau 
               
               
                   
               
               
                 3150 
                 gaccugagcu uuguuguaga cuauc 
               
               
                   
               
               
                 3151 
                 accugagcuu uguuguagac uauca 
               
               
                   
               
               
                 3152 
                 ccugagcuuu guuguagacu auc 
               
               
                   
               
               
                 3153 
                 cauuuuugac cuacaugugg 
               
               
                   
               
               
                 3154 
                 uuugaccuac auguggaaag 
               
               
                   
               
               
                 3155 
                 uacauuuuug accuacaugu ggaaag 
               
               
                   
               
               
                 3156 
                 ggucuccuua ccuauga 
               
               
                   
               
               
                 3157 
                 ucuuaccuau gacuauggau gaga 
               
               
                   
               
               
                 3158 
                 auuuuugacc uacaugggaa ag 
               
               
                   
               
               
                 3159 
                 uacgaguuga uugucggacc cag 
               
               
                   
               
               
                 3160 
                 guggucuccu uaccuaugac ugugg 
               
               
                   
               
               
                 3161 
                 ugucucagua aucuucuuac cuau 
               
               
                   
               
               
                 3162 
                 ugcauguucc agucguugug ugg 
               
               
                   
               
               
                 3163 
                 cacuauucca gucaaauagg ucugg 
               
               
                   
               
               
                 3164 
                 auuuaccaac cuucaggauc gagua 
               
               
                   
               
               
                 3165 
                 ggccuaaaac acauacacau a 
               
               
                   
               
               
                 3166 
                 gauagguggu aucaacaucu guaa 
               
               
                   
               
               
                 3167 
                 gauagguggu aucaacaucu g 
               
               
                   
               
               
                 3168 
                 cuuccuggau ggcuugaau 
               
               
                   
               
               
                 3169 
                 uguuguuguu uaugcucauu 
               
               
                   
               
               
                 3170 
                 guacauuaag auggacuuc 
               
               
                   
               
               
                 3171 
                 cuguugcagu aaucuaugag 
               
               
                   
               
               
                 3172 
                 ugcaguaauc uaugaguuuc 
               
               
                   
               
               
                 3173 
                 gagucuucua ggagccuu 
               
               
                   
               
               
                 3174 
                 ugccauuguu ucaucagcuc uuu 
               
               
                   
               
               
                 3175 
                 uccuguagga cauuggcagu 
               
               
                   
               
               
                 3176 
                 cuuggagucu ucuaggagcc 
               
               
                   
               
               
                 3177 
                 ccauuuugug aauguuuucu uuugaacauc 
               
               
                   
               
               
                 3178 
                 cccauuuugu gaauguuuuc uuuu 
               
               
                   
               
               
                 3179 
                 gaaaauugug cauuuaccca uuuu 
               
               
                   
               
               
                 3180 
                 uugugcauuu acccauuuug ug 
               
               
                   
               
               
                 3181 
                 cccugaggca uucccaucuu gaau 
               
               
                   
               
               
                 3182 
                 aggacuuacu ugcuuuguuu 
               
               
                   
               
               
                 3183 
                 cuugaauuua ggagauucau cug 
               
               
                   
               
               
                 3184 
                 caucuucuga uaauuuuccu guu 
               
               
                   
               
               
                 3185 
                 ccauuacagu ugucuguguu 
               
               
                   
               
               
                 3186 
                 ugacagccug ugaaaucugu gag 
               
               
                   
               
               
                 3187 
                 uaaucugccu cuucuuuugg 
               
               
                   
               
               
                 3188 
                 cagcaguagu ugucaucugc 
               
               
                   
               
               
                 3189 
                 gccugagcug aucugcuggc aucuugc 
               
               
                   
               
               
                 3190 
                 gccugagcug aucugcuggc aucuugcagu u 
               
               
                   
               
               
                 3191 
                 ucugcuggca ucuugc 
               
               
                   
               
               
                 3192 
                 gccgguugac uucauccugu gc 
               
               
                   
               
               
                 3193 
                 gucugcaucc aggaacaugg guc 
               
               
                   
               
               
                 3194 
                 uacuuacugu cuguagcucu uucu 
               
               
                   
               
               
                 3195 
                 cugcauccag gaacaugggu cc 
               
               
                   
               
               
                 3196 
                 guugaagauc ugauagccgg uuga 
               
               
                   
               
               
                 3197 
                 uaggugccug ccggcuu 
               
               
                   
               
               
                 3198 
                 uucagcugua gccacacc 
               
               
                   
               
               
                 3199 
                 cugaacugcu ggaaagucgc c 
               
               
                   
               
               
                 3200 
                 cuggcuucca aaugggaccu gaaaaagaac 
               
               
                   
               
               
                 3201 
                 caauuuuucc cacucaguau u 
               
               
                   
               
               
                 3202 
                 uugaaguucc uggagucuu 
               
               
                   
               
               
                 3203 
                 uccucaggag gcagcucuaa au 
               
               
                   
               
               
                 3204 
                 uggcucucuc ccaggg 
               
               
                   
               
               
                 3205 
                 gagauggcuc ucucccaggg acccugg 
               
               
                   
               
               
                 3206 
                 gggcacuuug uuuggcg 
               
               
                   
               
               
                 3207 
                 ggucccagca aguuguuug 
               
               
                   
               
               
                 3208 
                 ugggaugguc ccagcaaguu guuug 
               
               
                   
               
               
                 3209 
                 guagagcucu gucauuuugg g 
               
               
                   
               
               
                 3210 
                 gcucaagaga uccacugcaa aaaac 
               
               
                   
               
               
                 3211 
                 gccauacgua cguaucauaa acauuc 
               
               
                   
               
               
                 3212 
                 ucugcaggau auccaugggc ugguc 
               
               
                   
               
               
                 3213 
                 gauccucccu guucgucccc uauuaug 
               
               
                   
               
               
                 3214 
                 ugcuuuagac uccuguaccu gaua 
               
               
                   
               
               
                 3215 
                 ggcggccuuu guguugac 
               
               
                   
               
               
                 3216 
                 ggacaggccu uuauguucgu gcugc 
               
               
                   
               
               
                 3217 
                 ccuuuauguu cgugcugcu 
               
               
                   
               
               
                 3218 
                 ucaaggaaga uggcauuucu 
               
               
                   
               
               
                 3219 
                 ucaangaaga uggcauuucu 
               
               
                   
               
               
                 3220 
                 ucaagnaaga uggcauuucu 
               
               
                   
               
               
                 3221 
                 ucaaggaana uggcauuucu 
               
               
                   
               
               
                 3222 
                 ucaaggaaga ungcauuucu 
               
               
                   
               
               
                 3223 
                 ucaaggaaga ugncauuucu 
               
               
                   
               
               
                 3224 
                 ncaaggaaga uggcauuucu 
               
               
                   
               
               
                 3225 
                 ucaaggaaga nggcauuucu 
               
               
                   
               
               
                 3226 
                 ucaaggaaga uggcanuucu 
               
               
                   
               
               
                 3227 
                 ucaaggaaga uggcaunucu 
               
               
                   
               
               
                 3228 
                 ucaaggaaga uggcauuncu 
               
               
                   
               
               
                 3229 
                 ucaaggaaga uggcauuucn 
               
               
                   
               
               
                 3230 
                 ucnaggaaga uggcauuucu 
               
               
                   
               
               
                 3231 
                 ucanggaaga uggcauuucu 
               
               
                   
               
               
                 3232 
                 ucaaggnaga uggcauuucu 
               
               
                   
               
               
                 3233 
                 ucaagganga uggcauuucu 
               
               
                   
               
               
                 3234 
                 ucaaggaagn uggcauuucu 
               
               
                   
               
               
                 3235 
                 ucaaggaaga uggcnuuucu 
               
               
                   
               
               
                 3236 
                 uuugccncug cccaaugcca uccug 
               
               
                   
               
               
                 3237 
                 uuugccgcun cccaaugcca uccug 
               
               
                   
               
               
                 3238 
                 uuugccgcug cccaauncca uccug 
               
               
                   
               
               
                 3239 
                 uuunccgcug cccaaugcca uccug 
               
               
                   
               
               
                 3240 
                 uuugccgcug cccaaugcca uccun 
               
               
                   
               
               
                 3241 
                 nuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 3242 
                 unugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 3243 
                 uungccgcug cccaaugcca uccug 
               
               
                   
               
               
                 3244 
                 uuugccgcng cccaaugcca uccug 
               
               
                   
               
               
                 3245 
                 uuugccgcug cccanugcca uccug 
               
               
                   
               
               
                 3246 
                 uuugccgcug cccaaugccn uccug 
               
               
                   
               
               
                 3247 
                 uuunccncug cccaaugcca uccug 
               
               
                   
               
               
                 3248 
                 uuugccgcug cccaangcca uccug 
               
               
                   
               
               
                 3249 
                 uuugccgcug cccaaugcca nccug 
               
               
                   
               
               
                 3250 
                 uuugccgcug cccaaugcca uccng 
               
               
                   
               
               
                 3251 
                 uuugccgcug cccnaugcca uccug 
               
               
                   
               
               
                 3252 
                 ucagcuucun uuagccacug 
               
               
                   
               
               
                 3253 
                 ucagcuucug uuanccacug 
               
               
                   
               
               
                 3254 
                 ucancuucug uuagccacug 
               
               
                   
               
               
                 3255 
                 ucagcuucug uuagccacun 
               
               
                   
               
               
                 3256 
                 gnnnnnnnnn nnnngnnnn 
               
               
                   
               
               
                 3257 
                 nnngnnnnng nnngnnnnng 
               
               
                   
               
               
                 3258 
                 nnngnnnnnn gnnngnnnnn 
               
               
                   
               
               
                 3259 
                 nnnnnnnggn nnnngngnnn nnn 
               
               
                   
               
               
                 3260 
                 nnnnnngnnn nnngnnngnn nnn 
               
               
                   
               
               
                 3261 
                 nnnnnggnnn nngngnnnnn n 
               
               
                   
               
               
                 3262 
                 gnnnnnnnnn nnnngnnnng nnn 
               
               
                   
               
               
                 3263 
                 nnngnngnng nnnnnngnnn nnnng 
               
               
                   
               
               
                 3264 
                 nngnngnngn nnnnngnnnn nnng 
               
               
                   
               
               
                 3265 
                 nngnngnngn nnnnngnnnn nnngg 
               
               
                   
               
               
                 3266 
                 ngnngnngnn nnnngnnnnn nng 
               
               
                   
               
               
                 3267 
                 ngnngnngnn nnnngnnnnn nngg 
               
               
                   
               
               
                 3268 
                 gnngnngnnn nnngnnnnnn ng 
               
               
                   
               
               
                 3269 
                 nngnngnnnn nngnnnnnnn gg 
               
               
                   
               
               
                 3270 
                 nnngnnnnng nnnnnngnnn nnnng 
               
               
                   
               
               
                 3271 
                 nngnnngnng nngnnnnnng nnnnn 
               
               
                   
               
               
                 3272 
                 nngnnngnng nngnnnnnng nnnnnnnggn 
               
               
                   
               
               
                 3273 
                 nnnnggnngn nggnnnnnnn 
               
               
                   
               
               
                 3274 
                 nggnnnnnnn ngnnngg 
               
               
                   
               
               
                 3275 
                 nnnnnnggnn gnnggnnnnn nn 
               
               
                   
               
               
                 3276 
                 nnnnnnnnng gnngnnggnn nnnnn 
               
               
                   
               
               
                 3277 
                 nnnnngngnn nnnnnnnnnn gnn 
               
               
                   
               
               
                 3278 
                 nnngngnngg nnnnnnnnnn nnn 
               
               
                   
               
               
                 3279 
                 nnnnnnnggn ngnnggnnnn nnnngnnngg 
               
               
                   
               
               
                 3280 
                 nnnnnnnggn ngnnggnnnn nnnng 
               
               
                   
               
               
                 3281 
                 nnnnngnnng nnggnnnngn nnnnn 
               
               
                   
               
               
                 3282 
                 ggnnnngngn nnnnnnnnnn gg 
               
               
                   
               
               
                 3283 
                 nnnngnnngn nggnnnngnn nnnnn 
               
               
                   
               
               
                 3284 
                 nnnnnnnngg ggnngnnnnn gnnnn 
               
               
                   
               
               
                 3285 
                 ngnnnnngnn nnnngnnngn nggnn 
               
               
                   
               
               
                 3286 
                 nngnngnnnn nggnnnng 
               
               
                   
               
               
                 3287 
                 nnnnngnngn nnnnggnnnn gn 
               
               
                   
               
               
                 3288 
                 nnnnngnngn nnnnggnnnn gnn 
               
               
                   
               
               
                 3289 
                 nnnnngnngn nnnnggnnnn gnng 
               
               
                   
               
               
                 3290 
                 nngnngnnnn nggnnnngnn gg 
               
               
                   
               
               
                 3291 
                 nngnngnnnn nggnnnngnn ggn 
               
               
                   
               
               
                 3292 
                 nngnngnnnn nggnnnngnn ggng 
               
               
                   
               
               
                 3293 
                 nngnngnnnn nggnnnngnn ggngn 
               
               
                   
               
               
                 3294 
                 gnngnnnnng gnnnngnngg ngnnn 
               
               
                   
               
               
                 3295 
                 gnnnnnggnn nngnnggngn nnnng 
               
               
                   
               
               
                 3296 
                 nngnnnnngg nnnngnnggn gnnnnngnnn 
               
               
                   
               
               
                 3297 
                 nngnngnnnn nggnnnngnn ggngnnnnng 
               
               
                   
               
               
                 3298 
                 nnnnngnngn nnnnggnnnn gnnggngnnn nng 
               
               
                   
               
               
                 3299 
                 gngnnnnnnn nnnngnngnn nnnn 
               
               
                   
               
               
                 3300 
                 nnngngnnnn nnnnnnngnn gnnnn 
               
               
                   
               
               
                 3301 
                 ngnnnnnngn nggnnnnngg nngn 
               
               
                   
               
               
                 3302 
                 nnnnnngnng gnnnnnggnn gnng 
               
               
                   
               
               
                 3303 
                 nnnngnnggn nnnnggnngn ngnn 
               
               
                   
               
               
                 3304 
                 nngnnggnnn nnggnngnng nnnn 
               
               
                   
               
               
                 3305 
                 nnnnnnnnnn ngn 
               
               
                   
               
               
                 3306 
                 ngnnnnngnn ngnnn 
               
               
                   
               
               
                 3307 
                 nnnnnnnggn n 
               
               
                   
               
               
                 3308 
                 nnnngnnnnn ngnn 
               
               
                   
               
               
                 3309 
                 nnnnnnnnnn ngnnnngnnn 
               
               
                   
               
               
                 3310 
                 nnnnnnnnnn ngn 
               
               
                   
               
               
                 3311 
                 nnngnnnngn nn 
               
               
                   
               
               
                 3312 
                 nnngnngnng nnnnnngnnn 
               
               
                   
               
               
                 3313 
                 ngnngnnnnn ngnnnnnnng 
               
               
                   
               
               
                 3314 
                 gnngnngnnn nnngnnnnnn 
               
               
                   
               
               
                 3315 
                 nnggnngnng gnn 
               
               
                   
               
               
                 3316 
                 nggnngnngg nn 
               
               
                   
               
               
                 3317 
                 ngngnnggnn 
               
               
                   
               
               
                 3318 
                 ngnnggnnnn nnnn 
               
               
                   
               
               
                 3319 
                 nnnnnnnnnn 
               
               
                   
               
               
                 3320 
                 nnngngnnnn nnnnn 
               
               
                   
               
               
                 3321 
                 nngngnnnnn nnn 
               
               
                   
               
               
                 3322 
                 ngnnnnnnnn 
               
               
                   
               
               
                 3323 
                 ngnnnnnngn 
               
               
                   
               
               
                 3324 
                 gnngnnnnng gnnnngnngg 
               
               
                   
               
               
                 3325 
                 nnnnggnnnn gnnggngnnn 
               
               
                   
               
               
                 3326 
                 nnnnnggnnn ngnnggn 
               
               
                   
               
               
                 3327 
                 ngnnnnnnnn nnngnn 
               
               
                   
               
               
                 3328 
                 ngnnnnnnnn n 
               
               
                   
               
               
                 3329 
                 ngnnnnnngn nggnnnnngg nn 
               
               
                   
               
               
                 3330 
                 ngnnnnnngn n 
               
               
                   
               
               
                 3331 
                 nnnnngnngg n 
               
               
                   
               
               
                 3332 
                 nggnnnnngg nn 
               
               
                   
               
               
                 3333 
                 guugccuccg guucugaagg uguuc 
               
               
                   
               
               
                 3334 
                 guugnnunng guunugaagg uguun 
               
               
                   
               
               
                 3335 
                 caacaucaag gaagauggca uuucu 
               
               
                   
               
               
                 3336 
                 gccauuucuc aacagaucu 
               
               
                   
               
               
                 3337 
                 ucagcuucug uuagccacug 
               
               
                   
               
               
                 3338 
                 uuuguauuua gcauguuccc 
               
               
                   
               
               
                 3339 
                 auucucagga auuugugucu uuc 
               
               
                   
               
               
                 3340 
                 ccauuuguau uuagcauguu ccc 
               
               
                   
               
               
                 3341 
                 ucucaggaau uugugucuuu c 
               
               
                   
               
               
                 3342 
                 gccauuucuc aacagaucug uca 
               
               
                   
               
               
                 3343 
                 uuugccgcug cccaaugcca uccug 
               
               
                   
               
               
                 3344 
                 uugccgcugc ccaaugccau ccug 
               
               
                   
               
               
                 3345 
                 uugccgcugc ccaaugccau ccugg 
               
               
                   
               
               
                 3346 
                 ugccgcugcc caaugccauc cug 
               
               
                   
               
               
                 3347 
                 ugccgcugcc caaugccauc cugg 
               
               
                   
               
               
                 3348 
                 gccgcugccc aaugccaucc ug 
               
               
                   
               
               
                 3349 
                 ccgcugccca augccauccu gg 
               
               
                   
               
               
                 3350 
                 uuugccncug cccaaugcca uccug 
               
               
                   
               
               
                 3351 
                 caguuugccg cugcccaaug ccauc 
               
               
                   
               
               
                 3352 
                 caguuugccg cugcccaaug ccauccugga 
               
               
                   
               
               
                 3353 
                 ucaaggaaga uggcauuucu 
               
               
                   
               
               
                 3354 
                 uggcauuucu aguuugg 
               
               
                   
               
               
                 3355 
                 caucaaggaa gauggcauuu cu 
               
               
                   
               
               
                 3356 
                 caacaucaag gaagauggca uuucu 
               
               
                   
               
               
                 3357 
                 ccucugugau uuuauaacuu gau 
               
               
                   
               
               
                 3358 
                 ccagagcagg uaccuccaac auc 
               
               
                   
               
               
                 3359 
                 acaucaagga agauggcauu ucuaguuugg 
               
               
                   
               
               
                 3360 
                 acaucaagga agauggcauu ucuag 
               
               
                   
               
               
                 3361 
                 cucuugauug cuggucuugu uuuuc 
               
               
                   
               
               
                 3362 
                 gguaaugagu ucuuccaacu gg 
               
               
                   
               
               
                 3363 
                 ucuugauugc uggucuuguu uuuca 
               
               
                   
               
               
                 3364 
                 uuccaacugg ggacgccucu guucc 
               
               
                   
               
               
                 3365 
                 uguucuagcc ucuugauugc ugguc 
               
               
                   
               
               
                 3366 
                 cuguugccuc cgguucug 
               
               
                   
               
               
                 3367 
                 caacuguugc cuccgguucu ga 
               
               
                   
               
               
                 3368 
                 caacuguugc cuccgguucu gaa 
               
               
                   
               
               
                 3369 
                 caacuguugc cuccgguucu gaag 
               
               
                   
               
               
                 3370 
                 cuguugccuc cgguucugaa gg 
               
               
                   
               
               
                 3371 
                 cuguugccuc cgguucugaa ggu 
               
               
                   
               
               
                 3372 
                 cuguugccuc cgguucugaa ggug 
               
               
                   
               
               
                 3373 
                 cuguugccuc cgguucugaa ggugu 
               
               
                   
               
               
                 3374 
                 guugccuccg guucugaagg uguuc 
               
               
                   
               
               
                 3375 
                 gccuccgguu cugaaggugu ucuug 
               
               
                   
               
               
                 3376 
                 uugccuccgg uucugaaggu guucuuguac 
               
               
                   
               
               
                 3377 
                 cuguugccuc cgguucugaa gguguucuug 
               
               
                   
               
               
                 3378 
                 caacuguugc cuccgguucu gaagguguuc uug 
               
               
                   
               
               
                 3379 
                 gaguuucuuc caaagcagcc ucuc 
               
               
                   
               
               
                 3380 
                 uaugaguuuc uuccaaagca gccuc 
               
               
                   
               
               
                 3381 
                 agcauccugu aggacauugg cagu 
               
               
                   
               
               
                 3382 
                 cauccuguag gacauuggca guug 
               
               
                   
               
               
                 3383 
                 uccuguagga cauuggcagu uguu 
               
               
                   
               
               
                 3384 
                 cuguaggaca uuggcaguug uuuc 
               
               
                   
               
               
                 3385 
                 auuucucaac aga 
               
               
                   
               
               
                 3386 
                 agcuucuguu agcca 
               
               
                   
               
               
                 3387 
                 auucucagga a 
               
               
                   
               
               
                 3388 
                 auuuguauuu agca 
               
               
                   
               
               
                 3389 
                 auuucucaac agaucuguca 
               
               
                   
               
               
                 3390 
                 auuucucaac aga 
               
               
                   
               
               
                 3391 
                 acagaucugu ca 
               
               
                   
               
               
                 3392 
                 uuugccgcug cccaaugcca 
               
               
                   
               
               
                 3393 
                 cgcugcccaa ugccauccug 
               
               
                   
               
               
                 3394 
                 gccgcugccc aaugccaucc 
               
               
                   
               
               
                 3395 
                 aaggaagaug gca 
               
               
                   
               
               
                 3396 
                 aggaagaugg ca 
               
               
                   
               
               
                 3397 
                 agagcaggua 
               
               
                   
               
               
                 3398 
                 agcagguacc ucca 
               
               
                   
               
               
                 3399 
                 accuccaaca 
               
               
                   
               
               
                 3400 
                 aaugaguucu uccaa 
               
               
                   
               
               
                 3401 
                 augaguucuu cca 
               
               
                   
               
               
                 3402 
                 aguucuucca 
               
               
                   
               
               
                 3403 
                 agccucuuga 
               
               
                   
               
               
                 3404 
                 guugccuccg guucugaagg 
               
               
                   
               
               
                 3405 
                 cuccgguucu gaagguguuc 
               
               
                   
               
               
                 3406 
                 ccuccgguuc ugaaggu 
               
               
                   
               
               
                 3407 
                 aguuucuucc aaagca 
               
               
                   
               
               
                 3408 
                 aguuucuucc a 
               
               
                   
               
               
                 3409 
                 agcauccugu aggacauugg ca 
               
               
                   
               
               
                 3410 
                 agcauccugu a 
               
               
                   
               
               
                 3411 
                 auccuguagg a 
               
               
                   
               
               
                 3412 
                 aggacauugg ca 
               
               
                   
               
               
                 3413 
                 gguaaugagu unuunnaanu gg 
               
               
                   
               
               
                 3414 
                 ggnaangagn ncnnccaacn gg 
               
               
                   
               
               
                 3415 
                 ggunnugngu ucuuccnncu gg 
               
               
                   
               
               
                 3416 
                 ggnaangagn nnnnnnaann gg 
               
               
                   
               
               
                 3417 
                 ggunnugngu unuunnnnnu gg 
               
               
                   
               
               
                 3418 
                 ggnnnngngn ncnnccnncn gg 
               
               
                   
               
               
                 3419 
                 ggnnnngngn nnnnnnnnnn gg 
               
               
                   
               
               
                 3420 
                 uguunuagnn unuugauugn uggun 
               
               
                   
               
               
                 3421 
                 ngnncnagcc ncnnganngc nggnc 
               
               
                   
               
               
                 3422 
                 uguucungcc ucuugnuugc ugguc 
               
               
                   
               
               
                 3423 
                 ngnnnnagnn nnnnganngn nggnn 
               
               
                   
               
               
                 3424 
                 uguunungnn unuugnuugn uggun 
               
               
                   
               
               
                 3425 
                 ngnncnngcc ncnngnnngc nggnc 
               
               
                   
               
               
                 3426 
                 ngnnnnngnn nnnngnnngn nggnn 
               
               
                   
               
               
                 3427 
                 gaguuunuun naaagnagnn unun 
               
               
                   
               
               
                 3428 
                 gagnnncnnc caaagcagcc ncnc 
               
               
                   
               
               
                 3429 
                 gnguuucuuc cnnngcngcc ucuc 
               
               
                   
               
               
                 3430 
                 gagnnnnnnn naaagnagnn nnnn 
               
               
                   
               
               
                 3431 
                 gnguuunuun nnnngnngnn unun 
               
               
                   
               
               
                 3432 
                 gngnnncnnc cnnngcngcc ncnc 
               
               
                   
               
               
                 3433 
                 gngnnnnnnn nnnngnngnn nnnn 
               
               
                   
               
               
                 3434 
                 agnaunnugu agganauugg nagu 
               
               
                   
               
               
                 3435 
                 agcanccngn aggacanngg cagn 
               
               
                   
               
               
                 3436 
                 ngcnuccugu nggncnuugg cngu 
               
               
                   
               
               
                 3437 
                 agnannnngn aggananngg nagn 
               
               
                   
               
               
                 3438 
                 ngnnunnugu nggnnnuugg nngu 
               
               
                   
               
               
                 3439 
                 ngcnnccngn nggncnnngg cngn 
               
               
                   
               
               
                 3440 
                 ngnnnnnngn nggnnnnngg nngn 
               
               
                   
               
               
                 3441 
                 guugnnunng guunugaagg uguun 
               
               
                   
               
               
                 3442 
                 uuugnngnug nnnaaugnna unnug 
               
               
                   
               
               
                 3443 
                 nunuugauug nuggunuugu uuuun 
               
               
                   
               
               
                 3444 
                 ncaaggaaga nggcannncn 
               
               
                   
               
               
                 3445 
                 nnaaggaaga nggnannnnn 
               
               
                   
               
               
                 3446 
                 ncagcnncng nnagccacng 
               
               
                   
               
               
                 3447 
                 nnagnnnnng nnagnnanng 
               
               
                   
               
               
                 3448 
                 ucnnggnngn uggcnuuucu 
               
               
                   
               
               
                 3449 
                 ucngcuucug uungccncug 
               
               
                   
               
               
                 3450 
                 unagnuunug uuagnnanug 
               
               
                   
               
               
                 3451 
                 nnngnngnng nnnaangnna nnnng 
               
               
                   
               
               
                 3452 
                 uuugccgcug cccnnugccn uccug 
               
               
                   
               
               
                 3453 
                 gnngccnccg gnncngaagg ngnnc 
               
               
                   
               
               
                 3454 
                 gnngnnnnng gnnnngaagg ngnnn 
               
               
                   
               
               
                 3455 
                 guugccuccg guucugnngg uguuc 
               
               
                   
               
               
                 3456 
                 ggccaaaccn cggcnnaccn 
               
               
                   
               
               
                 3457 
                 unaaggaaga uggnauuunu 
               
               
                   
               
               
                 3458 
                 ggccaaaccu cggcuuaccu 
               
               
                   
               
               
                 3459 
                 guugnnuccg guunugaagg uguun 
               
               
                   
               
               
                 3460 
                 guugnnuccg guucugaagg uguuc 
               
               
                   
               
               
                 3461 
                 guugcnuccg guunugaagg uguun 
               
               
                   
               
               
                 3462 
                 ngaaaacgcc gccannncnc aacagancng 
               
               
                   
               
               
                 3463 
                 canaangaaa acgccgccan nncncaacag 
               
               
                   
               
               
                 3464 
                 ngnncagcnn cngnnagcca cngannaaan 
               
               
                   
               
               
                 3465 
                 cagnnngccg cngcccaang ccanccngga 
               
               
                   
               
               
                 3466 
                 nngccgcngc ccaangccan ccnggagnnc 
               
               
                   
               
               
                 3467 
                 ngcngcncnn nnccaggnnc aagngggana 
               
               
                   
               
               
                 3468 
                 cnnnnagnng cngcncnnnn ccaggnncaa 
               
               
                   
               
               
                 3469 
                 cnnnncnnnn agnngcngcn cnnnnccagg 
               
               
                   
               
               
                 3470 
                 nnagnngcng cncnnnncca ggnncaagng 
               
               
                   
               
               
                 3471 
                 cngnngccnc cggnncngaa ggngnncnng 
               
               
                   
               
               
                 3472 
                 caacngnngc cnccggnncn gaaggngnnc 
               
               
                   
               
               
                 3473 
                 nngccnccgg nncngaaggn gnncnngnac 
               
               
                   
               
               
                 3474 
                 tgaaaacgcc gccatttctc aacagatctg 
               
               
                   
               
               
                 3475 
                 cataatgaaa acgccgccat ttctcaacag 
               
               
                   
               
               
                 3476 
                 tgttcagctt ctgttagcca ctgattaaat 
               
               
                   
               
               
                 3477 
                 cagtttgccg ctgcccaatg ccatcctgga 
               
               
                   
               
               
                 3478 
                 ttgccgctgc ccaatgccat cctggagttc 
               
               
                   
               
               
                 3479 
                 tgctgctctt ttccaggttc aagtgggata 
               
               
                   
               
               
                 3480 
                 cttttagttg ctgctctttt ccaggttcaa 
               
               
                   
               
               
                 3481 
                 cttttctttt agttgctgct cttttccagg 
               
               
                   
               
               
                 3482 
                 ttagttgctg ctcttttcca ggttcaagtg 
               
               
                   
               
               
                 3483 
                 ctgttgcctc cggttctgaa ggtgttcttg 
               
               
                   
               
               
                 3484 
                 caactgttgc ctccggttct gaaggtgttc 
               
               
                   
               
               
                 3485 
                 ttgcctccgg ttctgaaggt gttcttgtac 
               
               
                   
               
               
                 3486 
                 rrrqrrkkr 
               
               
                   
               
               
                 3487 
                 rkkrrqrrr 
               
               
                   
               
               
                 3488 
                 rrrrrrrrrff 
               
               
                   
               
               
                 3489 
                 rrrrrffrrrr 
               
               
                   
               
               
                 3490 
                 rrrr 
               
               
                   
               
               
                 3491 
                 rrrrr 
               
               
                   
               
               
                 3492 
                 rrrrrr 
               
               
                   
               
               
                 3493 
                 rrrrrrr 
               
               
                   
               
               
                 3494 
                 rrrrrrrr 
               
               
                   
               
               
                 3495 
                 rrrrrrrrr 
               
               
                   
               
               
                 3496 
                 rahxrahxrahxrahxrahxrahxrahxrahx 
               
               
                   
               
               
                 3497 
                 rahxrrahxrrahxrrahxr 
               
               
                   
               
               
                 3498 
                 rahxrrahxrrahxrrahxrrahxr 
               
               
                   
               
               
                 3499 
                 rahxrrbrrahxrrbr 
               
               
                   
               
               
                 3500 
                 rarrarrarrarff 
               
               
                   
               
               
                 3501 
                 rgrrgrrgrrgrff 
               
               
                   
               
               
                 3502 
                 MQKLQLCVYIYLFMLIVAGPVDLNENSEQKENVEKEGLCNACTWRQN 
               
               
                   
                 TKSSRIEAIKIQILSKLRLETAPNISKDVIRQLLPKAPPLRELIDQYDVQRD 
               
               
                   
                 DSSDGSLEDDDYHATTETIITMPTESDFLMQVDGKPKCCFFKFSSKIQYN 
               
               
                   
                 KVVKAQLWIYLRPVETPTTVFVQILRLIKPMKDGTRYTGIRSLKLDMNP 
               
               
                   
                 GTGIWQSIDVKTVLQNWLKQPESNLGIEIKALDENGHDLAVTFPGPGED 
               
               
                   
                 GLNPFLEVKVTDTPKRSRRDFGLDCDEHSTESRCCRYPLTVDFEAFGW 
               
               
                   
                 DWIIAPKRYKANYCSGECEFVFLQKYPHTHLVHQANPRGSAGPCCTPT 
               
               
                   
                 KMSPINMLYFNGKEQIIYGKIPAMVVDRCGCS 
               
               
                   
               
               
                 3503 
                 MTAPWVALALLWGSLCAGSGRGEAETRECIYYNANWELERTNQSGLE 
               
               
                   
                 RCEGEQDKRLHCYASWRNSSGTIELVKKGCWLDDFNCYDRQECVATE 
               
               
                   
                 ENPQVYFCCCEGNFCNERFTHLPEAGGPEVTYEPPPTAPTLLTVLAYSL 
               
               
                   
                 LPIGGLSLIVLLAFWMYRHRKPPYGHVDIHEDPGPPPPSPLVGLKPLQLL 
               
               
                   
                 EIKARGRFGCVWKAQLMNDFVAVKIFPLQDKQSWQSEREIFSTPGMKH 
               
               
                   
                 ENLLQFIAAEKRGSNLEVELWLITAFHDKGSLTDYLKGNIITWNELCHV 
               
               
                   
                 AETMSRGLSYLHEDVPWCRGEGHKPSIAHRDFKSKNVLLKSDLTAVLA 
               
               
                   
                 DFGLAVRFEPGKPPGDTHGQVGTRRYMAPEVLEGAINFQRDAFLRIDM 
               
               
                   
                 YAMGLVLWELVSRCKAADGPVDEYMLPFEEEIGQHPSLEELQEVVVH 
               
               
                   
                 KKMRPTIKDHWLKHPGLAQLCVTIEECWDHDAEARLSAGCVEERVSLI 
               
               
                   
                 RRSVNGTTSDCLVSLVTSVTNVDLPPKESSI 
               
               
                   
               
            
           
         
       
     
     In embodiments, any uracil (U) or thymine (T) nucleotide in any of the modified antisense oligomer as described herein may be substituted with an X or n. In embodiments, each X or n is independently selected from uracil (U) or thymine (T).