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Not for further distribution unless allowed by the License or with the express written permission of Cambridge University Press.
https://doi.org/10.1017/S0317167100006788
https://doi.org/10.1017/S0317167100006788 Published online by Cambridge University Press
2022-04-12T19:44:34+00:00
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/GS0 gs
1 g
0 783 0 0 re
f
/GS1 gs
q
BT
/F0 1 Tf
9.5 0 0 9.5 52.024 717.0228 Tm
0 0 0 1 k
0.001 Tc
0.374 Tw
(It has been suggested that testing for G2019S LRRK2)Tj
-1.26316 -1.15789 TD
0 Tc
0.225 Tw
(mutation could be important in the management and genetic)Tj
T*
0.375 Tw
(counseling of patients with PD and commercial testing is)Tj
0 -1.1579 TD
0.118 Tw
[(available. )18(W)40(ith the wide variation in mutation rates it will be)]TJ
0 -1.15789 TD
0.245 Tw
(important to know how common mutations are occurring in)Tj
T*
0.135 Tw
(other non-selected PD population if mass screening was to be)Tj
0 -1.1579 TD
0.131 Tw
(considered. In addition there are other mutations found within)Tj
0 -1.15789 TD
-0.006 Tw
(the LRRK gene that cause PD although these are not as common)Tj
T*
0.136 Tw
(as the G2019S mutations.)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
6.27 0 0 6.27 141.5271 632.1578 Tm
0 0 0 1 k
(8,9)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
9.5 0 0 9.5 153.0321 629.0228 Tm
0 0 0 1 k
0.136 Tw
[(However)40(, LRRK2 is a lar)17(ge gene)]TJ
-11.89559 -1.1579 TD
0.166 Tw
(consisting of 51 exons (7642 bp mRNA) and therefore direct)Tj
0 -1.15789 TD
0.014 Tw
(sequencing of all the exons in all PD individuals is currently not)Tj
T*
0.025 Tw
(practical and a better screening method is needed. )Tj
1.26316 -1.1579 TD
0.017 Tc
0.358 Tw
[(W)80(e chose denaturing high-performance liquid chroma-)]TJ
-1.26316 -1.15789 TD
0 Tc
0.142 Tw
(tography (DHPLC) to screen an unselected PD population for)Tj
T*
0.225 Tw
(possible mutations occurring in the seven exons where most)Tj
0 -1.1579 TD
-0.021 Tw
[(mutations in LRRK2 are found. )18(The advantage of DHPLC is that)]TJ
0 -1.15789 TD
0.085 Tw
(it can be used as a high throughput screening method to detect)Tj
T*
-0.023 Tw
[(sequence variants with great sensitivity and doesn\325)18(t have the cost)]TJ
0 -1.1579 TD
0.006 Tc
0.369 Tw
(associated with having to directly sequence all individual)Tj
0 -1.15789 TD
0 Tc
0 Tw
(samples.)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F1 1 Tf
9.5 0 0 9.5 40.024 486.0228 Tm
0 0 0 1 k
(M)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F1 1 Tf
7.125 0 0 7.125 48.9906 486.0228 Tm
0 0 0 1 k
0.0015 Tc
(E)Tj
0.6675 -0.00001 TD
0.001 Tc
(THODS)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
9.5 0 0 9.5 52.024 471.0228 Tm
0 0 0 1 k
0.032 Tw
(This study was approved by the Ottawa Hospital and McGill)Tj
-1.26316 -1.1579 TD
0.011 Tw
[(University Ethics Review Boards. )18(W)40(ritten and informed consent)]TJ
T*
-0.028 Tw
(was obtained from all participants. Blood samples were collected)Tj
0 -1.15789 TD
0.197 Tw
(from PD patients and neurologically normal controls \(mainly)Tj
0 -1.1579 TD
0.117 Tw
(spouses\) attending one of two clinics \(one in Ottawa, Ontario,)Tj
T*
0.013 Tw
(one in Montreal, Quebec, Canada\) from 2001-2004 as part of an)Tj
0 -1.15789 TD
-0.029 Tw
(ongoing ef)Tj
4.25754 0 TD
(fort to explore the role of genetics in PD in a Canadian)Tj
-4.25754 -1.1579 TD
0 Tw
(cohort. )Tj
3.23465 0 TD
0.235 Tw
(All participants completed a structured questionnaire,)Tj
-3.23465 -1.1579 TD
0.287 Tw
(underwent a history and examination by a neurologist with)Tj
0 -1.15789 TD
0.01 Tw
(extensive experience in PD \(M.P)Tj
13.12015 0 TD
-0.0001 Tc
(.)Tj
0.51031 0 Td
0 Tc
(or D.G.\). Diagnosis of PD and)Tj
-13.63046 -1.1579 TD
-0.032 Tw
(exclusionary criteria suggestive of another disease were based on)Tj
T*
0.025 Tw
(previously published criteria.)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
6.27 0 0 6.27 151.5558 353.1578 Tm
0 0 0 1 k
(10)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
9.5 0 0 9.5 52.024 339.0228 Tm
0 0 0 1 k
0.106 Tw
[(Genomic DNA)-301(from blood samples of 230 PD patients and)]TJ
-1.26316 -1.1579 TD
0.287 Tw
(129 normal controls was extracted and processed using the)Tj
T*
0.061 Tw
(QIAmp DNA)Tj
5.78807 0 TD
(Blood Mini Kit \(QIAGEN Inc. Mississauga, ON,)Tj
-5.78807 -1.1579 TD
0 Tw
(Canada\). )Tj
3.78461 0 TD
0.008 Tw
(All samples were individually amplified in a 50ul PCR)Tj
-3.78461 -1.1579 TD
0.28 Tw
[(containing 50-100ng genomic DNA, 10mM )18(T)35(ris-Cl pH 8.0,)]TJ
0 -1.15789 TD
0.01 Tc
0.364 Tw
(0.2mM dNTPs,1.5mM MgCl)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
6.27 0 0 6.27 160.2487 280.8877 Tm
0 0 0 1 k
(2)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
9.5 0 0 9.5 163.4497 284.0228 Tm
0 0 0 1 k
0.0104 Tc
(,)Tj
0.88534 0 Td
0.01 Tc
0.364 Tw
(10uM forward and reverse)Tj
-13.87752 -1.1579 TD
0 Tc
0.311 Tw
[(primers, and 5U )18(T)70(aq DNA)-506(polymerase. PCR in a 96 well)]TJ
0 -1.15789 TD
-0.012 Tw
(microplate was carried out on a thermal cycler \(Thermo Electron)Tj
0 -1.1579 TD
0.035 Tw
[(Corp., )18(W)80(altham, MA, U.S.A.\) with the conditions of 94\241C for 3)]TJ
0 -1.15789 TD
-0.02 Tw
(min, 37 cycles at 94\241C for 45 s; 55\241C for 30 s; 72\241C for 30s; and)Tj
-0.0001 Tc
(a)'
0.72023 0 Td
0 Tc
0.026 Tw
(final extension at 72 )Tj
8.49185 0.00001 TD
(\241C for 10 min. Primers were designed to)Tj
-9.21208 -1.15791 TD
0.343 Tw
(screen the following known LRKK2 mutations: exon 19 -)Tj
0 -1.15789 TD
0.264 Tw
(R793M, exon 24 - L1)Tj
10.22869 0.00001 TD
(1)Tj
0.46314 0.00001 TD
[(14L, exon 25 - I1)37(122V)129(, exon 31 -)]TJ
-10.69182 -1.15791 TD
0.233 Tw
[(R1441C, R1441G, R1441H, exon 35 - )37(Y1699C, exon 38 -)]TJ
0 -1.1579 TD
-0.028 Tw
[(M1869T)74(, and exon 41 - G2019S, I2020T)74(. Positive DNA)-167(controls,)]TJ
0 -1.15789 TD
0.077 Tw
[(except for LRRK2 exon 19, were kindly donated by M. Farrer)55(.)]TJ
T*
0.293 Tw
(After confirming the presence of the amplicons on a 1.0%)Tj
0 -1.1579 TD
0.092 Tw
(agarose gel, all samples were denatured at 94\241C for 2 min and)Tj
0 -1.15789 TD
0.097 Tw
(slowly cooled to 25\241C at a decreasing rate of 1\241C per cycle to)Tj
T*
0.372 Tw
[(encourage any possible heteroduplex formation. )18(The initial)]TJ
0 -1.1579 TD
0.097 Tw
[(mutation detection was carried out on a )18(T)35(ransgenomics )18(W)111(A)129(VE)]TJ
0 -1.15789 TD
0.076 Tw
(DHPLC \(T)Tj
4.51192 0.00001 TD
[(ransition )18(T)70(echnologies, )17(T)70(oronto, ON, Canada\). Each)]TJ
-4.51192 -1.1579 TD
0.273 Tw
(of the samples including positive and normal controls were)Tj
T*
0.149 Tw
[(injected separately onto a DNASep column. )18(The temperatures)]TJ
0 -1.15789 TD
0.225 Tw
(required for the detection of heteroduplex formation of each)Tj
28.33011 67.57894 TD
0.235 Tw
[(amplicon were predicted using the )18(W)80(avemaker version 1.6.2)]TJ
0 -1.15789 TD
-0.021 Tw
[(software. DNA)-174(fragments were eluted from the DNASep column)]TJ
T*
0.244 Tw
[(at a predetermined elution gradient using )18(W)80(avemaker in the)]TJ
0 -1.1579 TD
0.358 Tw
[(range of 55.0 to 58.5% Buf)18(fer B \(0.1M )18(TEAA)-554(and 25%)]TJ
0 -1.15789 TD
0.052 Tw
[(acetonitrile\) at a flow rate of 0.9ml per minute. )18(The profiles for)]TJ
T*
0.066 Tw
(each sample were visually analyzed and clustered using default)Tj
0 -1.1579 TD
-0.034 Tw
[(values in )18(W)80(avemaker)55(. )17(The PCR products of any variants detected)]TJ
0 -1.15789 TD
0.02 Tc
0.443 Tw
[(with the DHPLC were treated with ExoSap-IT)-695(\(USB)]TJ
T*
0 Tc
0.16 Tw
(Corporation, Cleveland, OH, U.S.A.\) at 37 for 20 min before)Tj
0 -1.1579 TD
-0.024 Tw
[(proceeding with BigDye )18(T)70(erminator v3.1 cycle sequencing on an)]TJ
0 -1.15789 TD
0.132 Tw
(ABI 3130)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F3 1 Tf
9.5 0 0 9.5 348.1454 607.0228 Tm
0 0 0 1 k
(xl)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
9.5 0 0 9.5 358.6307 607.0228 Tm
0 0 0 1 k
0.132 Tw
[(Genetic )55(Analyzer \(Foster City)65(, CA, U.S.A.\) using)]TJ
-5.20744 -1.15789 TD
0.025 Tw
(both PCR forward and reverse amplicon primers. )Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F1 1 Tf
9.5 0 0 9.5 309.16 574.0228 Tm
0 0 0 1 k
(R)Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F1 1 Tf
7.125 0 0 7.125 316.0183 574.0228 Tm
0 0 0 1 k
0.0013 Tc
(E)Tj
0.66727 -0.00001 TD
0.001 Tc
[(SUL)93(T)-1(S)]TJ
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
9.5 0 0 9.5 321.16 559.0228 Tm
0 0 0 1 k
-0.032 Tw
(In our PD cohort of 230 patients, 34% had at least one relative)Tj
-1.26316 -1.15789 TD
0.054 Tw
[(with PD, 14% had at least one first degree relative af)18(fected and)]TJ
0 -1.1579 TD
0.069 Tw
[(2% had 3 or more af)18(fected relatives. One hundred forty six PD)]TJ
0 -1.15789 TD
0.135 Tw
(patients were men while 84 patients were women; 63 patients)Tj
T*
0.045 Tw
[(had an age of onset less than or equal to 50 years. )18(The average)]TJ
0 -1.1579 TD
0.119 Tw
(age at onset of PD was 57.7 years (range 31 to 92 years old).)Tj
0 -1.15789 TD
0.343 Tw
(Almost all individuals were of North or Central European)Tj
0 -1.1579 TD
0.03 Tw
(ancestry (97%) with 127 (55%) of those people being of French)Tj
0 -1.15789 TD
-0.032 Tw
(Canadian heritage. )Tj
7.66416 0 TD
(The average age for controls when the sample)Tj
-7.66416 -1.1579 TD
0.025 Tw
(was drawn was 63.5 years old (range 24 to 86 years old). )Tj
1.26316 -1.1579 TD
0.06 Tw
(The initial mutation screening on the DHPLC identified 120)Tj
-1.26316 -1.15789 TD
0.18 Tw
(PD and 7 normal control samples with heteroduplex profiles.)Tj
0 -1.1579 TD
0.041 Tw
(The sequencing of these samples revealed 5 novel and 2 known)Tj
T*
0.003 Tw
[(intronic sequence variants \(T)70(able\). )17(W)80(e were unable to detect any)]TJ
0 -1.15789 TD
0.308 Tw
(of the known mutations or identify novel mutations within)Tj
0 -1.1579 TD
0.025 Tw
(LRRK2 exons 19, 24, 25, 31, 35, 38, and 41 \(T)Tj
19.06716 0 TD
(able\). )Tj
ET
Q
/GS2 gs
/GS1 gs
q
BT
/F1 1 Tf
9.5 0 0 9.5 308.8 317.0141 Tm
0 0 0 1 k
(T)Tj
0.5752 0 TD
0.001 Tc
0.229 Tw
(able: LRRK2 variants excluded or)Tj
16.09422 0 TD
(identified in our)Tj
7.8058 0 TD
0.002 Tc
0 Tw
(PD)Tj
-23.21206 -1.15791 TD
0.018 Tc
0.358 Tw
[(population consisting of 460 chr)19(omosomes and 258)]TJ
0 -1.15789 TD
0.001 Tc
0 Tw
(contr)Tj
2.25855 0 TD
0.025 Tw
[(ol chr)19(omosomes)]TJ
ET
1 w
0 0 0 1 K
307.8 117.9169 m
554.976 117.9169 l
S
307.8 330.575 m
554.976 330.575 l
S
0.5 w
307.8 287.575 m
554.976 287.575 l
S
Q
/GS2 gs
/GS1 gs
q
BT
/F0 1 Tf
8.5 0 0 8.5 308.8 106.5072 Tm
0 0 0 1 k
0.025 Tw
(Previously identified coding mutations are highlighted in bold. )Tj
0 -1.29412 TD
((1) Nucleotide position based on GenBank )Tj
17.6982 0.00001 TD
[(A)92(Y79251)37(1.1 (2) )55(Amino)]TJ
-17.6982 -1.29412 TD
(acid position based on GenPept )Tj
12.92799 0.00001 TD
0 Tw
(AA)Tj
1.31494 0.00001 TD
0.025 Tw
(V63975.1; nd: not determined )Tj
-14.24293 -1.29414 TD
(*novel variants)Tj
ET
/GS2 gs
q
307.8 118.2169 m
307.8 283.537 l
554.976 283.537 l
554.976 118.2169 l
W n
q
447.5448 -164.2951 55.5024 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 457.812 277.9793 Tm
0 g
0.011 Tc
0 Tw
[(P)2(D)-267(pop)-1(ul)17(a)-1(t)19(i)17(o)-1(n)]TJ
ET
Q
q
503.0472 -164.2951 55.2048 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 508.1064 277.9793 Tm
0 g
0.011 Tc
0 Tw
[(C)3(ont)18(r)20(ol)-254(po)-1(pul)16(at)-8(i)16(on)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 346.3608 277.9793 Tm
0 g
0.011 Tc
0 Tw
[(N)3(uc)-3(l)17(eot)18(i)17(de)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 349.3368 271.6841 Tm
0 g
0.011 Tc
0 Tw
[(c)-3(han)-1(ge)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
3.72 0 0 3.66 367.788 274.4657 Tm
0 g
(1)Tj
ET
Q
q
383.1144 -164.2951 36.1584 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 387.5784 274.9049 Tm
0 g
0.011 Tc
0 Tw
[(db)-1(S)2(N)4(P)-268(r)20(s)-3(#)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 429.54 277.9793 Tm
0 g
0.009 Tc
0 Tw
(AA)Tj
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 422.9928 271.6841 Tm
0 g
0.011 Tc
0 Tw
[(c)-3(han)-1(ge)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
W n
BT
/F8 1 Tf
3.72 0 0 3.66 441.444 274.4657 Tm
0 g
(2)Tj
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 451.4136 268.9025 Tm
0 g
0.011 Tc
0 Tw
[(v)-3(ar)20(i)17(a)-1(nt)]TJ
ET
Q
q
471.7992 -164.2951 31.248 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 475.2216 268.9025 Tm
0 g
0.011 Tc
0 Tw
[(f)19(r)19(eq)-1(ue)-1(nc)-2(y)]TJ
ET
Q
q
503.0472 -164.2951 24.1056 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 506.7672 268.9025 Tm
0 g
0.011 Tc
0 Tw
[(v)-3(ar)20(i)17(a)-1(nt)]TJ
ET
Q
q
527.1528 -164.2951 31.0992 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 530.4264 268.9025 Tm
0 g
0.011 Tc
0 Tw
[(f)19(r)19(eq)-1(uen)-1(c)-2(y)]TJ
ET
Q
q
307.2264 -164.2951 28.7184 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 311.244 259.8257 Tm
0 g
-0.008 Tc
0 Tw
[(In)-20(tro)-19(n)-19(1)-20(8)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 341.3016 259.8257 Tm
0 g
0.009 Tc
0 Tw
[(I)17(VS1)-2(8)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 356.4792 259.8257 Tm
0 g
(-)Tj
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 358.2648 259.8257 Tm
0 g
0.011 Tc
0 Tw
[(27)-1(A)2(>)1(G)5(*)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 452.7528 259.8257 Tm
0 g
0.011 Tc
0 Tw
[(1/)18(46)-1(0)]TJ
ET
Q
q
471.7992 -164.2951 31.248 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 479.5368 259.8257 Tm
0 g
0.011 Tc
0 Tw
[(0.)18(22)-1(%)]TJ
ET
Q
q
503.0472 -164.2951 24.1056 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 513.4632 259.8257 Tm
0 g
(0)Tj
ET
Q
q
527.1528 -164.2951 31.0992 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 541.14 259.8257 Tm
0 g
(0)Tj
ET
Q
q
0 g
307.2264 267.4385 28.7184 0.2928 re
f
335.9448 267.4385 0.2976 0.2928 re
f
336.2424 267.4385 46.872 0.2928 re
f
383.1144 267.4385 0.2976 0.2928 re
f
383.412 267.4385 35.8608 0.2928 re
f
419.2728 267.4385 0.2976 0.2928 re
f
419.5704 267.4385 27.9744 0.2928 re
f
447.5448 267.4385 0.2976 0.2928 re
f
447.8424 267.4385 23.9568 0.2928 re
f
471.7992 267.4385 0.2976 0.2928 re
f
472.0968 267.4385 30.9504 0.2928 re
f
503.0472 267.4385 0.2976 0.2928 re
f
503.3448 267.4385 23.808 0.2928 re
f
527.1528 267.4385 0.2976 0.2928 re
f
527.4504 267.4385 30.8016 0.2928 re
f
q
307.2264 -164.2951 28.7184 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 311.244 251.0417 Tm
-0.008 Tc
0 Tw
[(In)-20(tro)-19(n)-19(1)-20(8)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 341.5992 251.0417 Tm
0.009 Tc
0 Tw
[(I)17(VS1)-2(8)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 356.7768 251.0417 Tm
(-)Tj
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 358.5624 251.0417 Tm
0.011 Tc
0 Tw
[(22)-1(C)4(>T*)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 451.116 251.0417 Tm
0.011 Tc
0 Tw
[(13)-1(/)19(4)-1(60)]TJ
ET
Q
q
471.7992 -164.2951 31.248 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 479.5368 251.0417 Tm
0.011 Tc
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[(2.)18(83)-1(%)]TJ
ET
Q
q
503.0472 -164.2951 24.1056 483.1201 re
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BT
/F8 1 Tf
5.5056 0 0 5.4168 508.1064 251.0417 Tm
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[(2/)18(25)-1(8)]TJ
ET
Q
q
527.1528 -164.2951 31.0992 483.1201 re
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BT
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[(0.)18(78)-1(%)]TJ
ET
Q
q
307.2264 -164.2951 28.7184 483.1201 re
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BT
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[(E)-1(XO)2(N1)-3(9)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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[(c.)18(23)-1(78)-1(G)5(>)1(T)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
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BT
/F9 1 Tf
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0.011 Tc
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[(R)3(793)-1(M)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
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BT
/F8 1 Tf
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ET
Q
q
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BT
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Q
q
503.0472 -164.2951 24.1056 483.1201 re
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BT
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ET
Q
q
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(nd)Tj
ET
Q
q
307.2264 -164.2951 28.7184 483.1201 re
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BT
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[(In)-20(tro)-19(n)-19(1)-20(9)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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5.5056 0 0 5.4168 340.7064 233.4737 Tm
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[(IV)-17(S)]TJ
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Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
/F8 1 Tf
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[(19)-1(+)1(6)-1(4A)2(>C)4(*)]TJ
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Q
q
447.5448 -164.2951 24.2544 483.1201 re
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BT
/F8 1 Tf
5.5056 0 0 5.4168 452.7528 233.4737 Tm
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[(1/)18(46)-1(0)]TJ
ET
Q
q
471.7992 -164.2951 31.248 483.1201 re
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BT
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[(0.)18(22)-1(%)]TJ
ET
Q
q
503.0472 -164.2951 24.1056 483.1201 re
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BT
/F8 1 Tf
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ET
Q
q
527.1528 -164.2951 31.0992 483.1201 re
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BT
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Q
q
307.2264 -164.2951 28.7184 483.1201 re
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BT
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5.5056 0 0 5.4168 310.5 224.6897 Tm
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[(E)-1(XO)2(N2)-3(4)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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5.5056 0 0 5.4168 345.1704 224.6897 Tm
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[(c.)18(33)-1(42)-1(A)4(>G)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
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BT
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5.5056 0 0 5.4168 423.588 224.6897 Tm
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[(L11)-1(14L)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
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BT
/F8 1 Tf
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Q
q
471.7992 -164.2951 31.248 483.1201 re
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Q
q
503.0472 -164.2951 24.1056 483.1201 re
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ET
Q
q
527.1528 -164.2951 31.0992 483.1201 re
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(nd)Tj
ET
Q
q
307.2264 -164.2951 28.7184 483.1201 re
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BT
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5.5056 0 0 5.4168 310.5 215.9057 Tm
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[(E)-1(XO)2(N2)-3(5)]TJ
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Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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[(c.)18(33)-1(64)-1(A)4(>G)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
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BT
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5.5056 0 0 5.4168 424.4808 215.9057 Tm
0.012 Tc
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[(I)20(11)1(22)1(V)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
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BT
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Q
q
471.7992 -164.2951 31.248 483.1201 re
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Q
q
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ET
Q
q
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Q
q
307.2264 -164.2951 28.7184 483.1201 re
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5.5056 0 0 5.4168 310.5 207.1217 Tm
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[(E)-1(XO)2(N3)-3(1)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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5.5056 0 0 5.4168 345.6168 207.1217 Tm
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[(c.)18(43)-1(21)-1(C)4(>T)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
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BT
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5.5056 0 0 5.4168 422.9928 207.1217 Tm
0.011 Tc
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[(R)3(144)-1(1C)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
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BT
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Q
q
471.7992 -164.2951 31.248 483.1201 re
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BT
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Q
q
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ET
Q
q
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BT
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ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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5.5056 0 0 5.4168 345.1704 198.3377 Tm
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[(c.)18(43)-1(21)-1(C)4(>G)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
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BT
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0.011 Tc
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[(R)3(144)-1(1G)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
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BT
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Q
q
471.7992 -164.2951 31.248 483.1201 re
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BT
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Q
q
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Q
q
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Q
q
335.9448 -164.2951 47.1696 483.1201 re
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5.5056 0 0 5.4168 345.1704 189.5537 Tm
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[(c.)18(43)-1(21)-1(G)5(>)1(A)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
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BT
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[(R)3(144)-1(1H)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
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BT
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Q
q
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BT
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Q
q
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Q
q
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Q
q
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BT
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ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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[(c.)18(50)-1(96)-1(A)4(>G)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
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BT
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0.011 Tc
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[(Y)2(16)-1(99C)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
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BT
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Q
q
471.7992 -164.2951 31.248 483.1201 re
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BT
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Q
q
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Q
q
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Q
q
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BT
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-0.008 Tc
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[(In)-20(tro)-19(n)-19(3)-20(5)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 342.0456 171.9857 Tm
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ET
Q
q
383.1144 -164.2951 36.1584 483.1201 re
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BT
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[(r)20(s)-3(73)-1(072)-1(76)]TJ
ET
Q
387.876 170.9609 26.4864 0.4392 re
f
q
447.5448 -164.2951 24.2544 483.1201 re
W n
BT
/F8 1 Tf
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ET
Q
q
471.7992 -164.2951 31.248 483.1201 re
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BT
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ET
Q
q
503.0472 -164.2951 24.1056 483.1201 re
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BT
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ET
Q
q
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BT
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ET
Q
q
307.2264 -164.2951 28.7184 483.1201 re
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BT
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5.5056 0 0 5.4168 311.244 163.2017 Tm
-0.008 Tc
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[(In)-20(tro)-19(n)-19(3)-20(7)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
/F8 1 Tf
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0.009 Tc
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[(I)17(VS3)-2(7)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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5.5056 0 0 5.4168 355.2888 163.2017 Tm
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ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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5.5056 0 0 5.4168 357.0744 163.2017 Tm
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[(10)-1(3A)2(>)1(T*)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
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BT
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5.5056 0 0 5.4168 452.7528 163.2017 Tm
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[(3/)18(46)-1(0)]TJ
ET
Q
q
471.7992 -164.2951 31.248 483.1201 re
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BT
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[(0.)18(65)-1(%)]TJ
ET
Q
q
503.0472 -164.2951 24.1056 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 508.1064 163.2017 Tm
0.011 Tc
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[(2/)18(25)-1(8)]TJ
ET
Q
q
527.1528 -164.2951 31.0992 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 534.7416 163.2017 Tm
0.011 Tc
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[(0.)18(78)-1(%)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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0.009 Tc
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[(I)17(VS3)-2(7)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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5.5056 0 0 5.4168 357.9672 154.4177 Tm
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Q
q
335.9448 -164.2951 47.1696 483.1201 re
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BT
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5.5056 0 0 5.4168 359.7528 154.4177 Tm
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ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
W n
BT
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[(1/)18(46)-1(0)]TJ
ET
Q
q
471.7992 -164.2951 31.248 483.1201 re
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BT
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[(0.)18(22)-1(%)]TJ
ET
Q
q
503.0472 -164.2951 24.1056 483.1201 re
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BT
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[(1/)18(25)-1(8)]TJ
ET
Q
q
527.1528 -164.2951 31.0992 483.1201 re
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BT
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ET
Q
q
307.2264 -164.2951 28.7184 483.1201 re
W n
BT
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5.5056 0 0 5.4168 310.5 145.6337 Tm
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[(E)-1(XO)2(N3)-3(8)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F9 1 Tf
5.5056 0 0 5.4168 345.6168 145.6337 Tm
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[(c.)18(56)-1(06)-1(T)1(>C)]TJ
ET
Q
q
419.2728 -164.2951 28.272 483.1201 re
W n
BT
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5.5056 0 0 5.4168 422.9928 145.6337 Tm
0.011 Tc
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[(M)6(18)-1(69T)]TJ
ET
Q
q
447.5448 -164.2951 24.2544 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 458.1096 145.6337 Tm
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ET
Q
q
471.7992 -164.2951 31.248 483.1201 re
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BT
/F8 1 Tf
5.5056 0 0 5.4168 485.9352 145.6337 Tm
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ET
Q
q
503.0472 -164.2951 24.1056 483.1201 re
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BT
/F8 1 Tf
5.5056 0 0 5.4168 511.9752 145.6337 Tm
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ET
Q
q
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W n
BT
/F8 1 Tf
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(nd)Tj
ET
Q
q
307.2264 -164.2951 28.7184 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 311.244 136.8497 Tm
-0.008 Tc
0 Tw
[(In)-20(tro)-19(n)-19(3)-20(8)]TJ
ET
Q
q
335.9448 -164.2951 47.1696 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 341.5992 136.8497 Tm
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[(I)19(V)2(S)2(38)-1(+)1(3)-1(5G)5(>A)]TJ
ET
Q
q
383.1144 -164.2951 36.1584 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 386.388 136.8497 Tm
0.011 Tc
0 Tw
[(r)20(s)-3(17)-1(484)-1(34)-1(2)]TJ
ET
Q
386.388 135.8249 29.4624 0.4392 re
f
q
447.5448 -164.2951 24.2544 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 451.116 136.8497 Tm
0.011 Tc
0 Tw
[(11)-1(/)19(4)-1(60)]TJ
ET
Q
q
471.7992 -164.2951 31.248 483.1201 re
W n
BT
/F8 1 Tf
5.5056 0 0 5.4168 479.5368 136.8497 Tm
0.011 Tc
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[(2.)18(39)-1(%)]TJ
ET
Q
q
503.0472 -164.2951 24.1056 483.1201 re
W n
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