437:. The metabolites produced by CYP ω-hydroxylases, particularly 20-HETE, have been found to have pleiotropic effects in inflammation and many inflammation-associated diseases. These enzymes are part of the larger family of CYP enzymes that mediate oxidation reactions in the human body. They are mainly expressed in various tissues and organs, including the liver, kidney, lung, endothelial cells, platelets, and immunocytes. The expression levels of CYP ω-hydroxylases can be influenced by gender and inflammatory stimuli.
77:(e.g. drugs, industrial toxins) and naturally occurring endobiotic (e.g. cholesterol) substrates, most of which are not fatty acids. The CYP450 omega hydroxylases are accordingly better viewed as a subset of monooxygenases that have the ability to hydroxylate fatty acids. While once regarded as functioning mainly in the
294:ω-hydroxylates extremely long very long chain fatty acids, i.e. fatty acids that are 28 or more carbons long. The ω-hydroxylation of these special fatty acids is critical to creating and maintaining the skins water barrier function; autosomal recessive inactivating mutations of CYP4F22 are associated with the
445:
Inflammation-related diseases involve an imbalance between pro-inflammatory and anti-inflammatory mediators. CYP ω-hydroxylase-mediated eicosanoids can function as pro-inflammatory and anti-inflammatory mediators depending on the context. For example, 20-HETE has been shown to promote vascular
446:
inflammation by activating endothelial cells and induction of inflammatory cytokines. Up-regulation of CYP ω-hydroxylases may be a pathogenic mechanism in many inflammation-associated diseases. Targeting these enzymes may hold therapeutic potential for treating such conditions.
134:
CYP450 enzymes belong to a superfamily which in humans is composed of at least 57 CYPs; within this superfamily, members of six CYP4A subfamilies, (which are CYP4A, CYP4B, CYP4F, CYP4V, CYP4X, and CYP4z) possess ω-hydroxylase activity viz., CYP4A, CYP4B, and CYP4F
225:
3) Members of the CYP4F family, i.e. CYPA11, CYP4F2, CYP4F3A, CYP4F3B, and CYP4F11, as well as CYP2U1 ω-hydroxylate long chain fatty acids, i.e. fatty acids that are 18 to 20 carbons long. These hydroxyl fatty acids are then serially metabolized by
151:, i.e. fatty acids that are 7-9 carbons long; CYP4B1 is far more weakly expressed in humans than that expressed in other mammals that were tested. Subsequent to their ω-hydroxylation, these products are converted to their acyl
274:
where they may undergo chain shortening or, as acylcarnitine derivatives or free acids, transferred to mitochondria for complete beta oxidation. The chain-shortened products of peroxisome metabolism may also be converted to
242:
where they may undergo chain shortening or, as acylcarnitine derivatives or free acids, transferred to mitochondria for complete beta oxidation. The chain-shortened products of peroxisome metabolism may also be converted to
97:
The omega oxygenases metabolize fatty acids (RH) by adding a hydroxyl (OH) to their terminal (i.e. furthest from the fatty acids' carboxy residue) carbons; in the reaction, the two atoms of molecular oxygen(O
81:
of dietary fatty acids, the omega oxygenases are now considered critical in the production or break-down of fatty acid-derived mediators which are made by cells and act within their cells of origin as
352:(20-HETE). Animal and human tissue studies suggest that the CYP-dependent production of 20-HETE contributes to the regulation of blood pressure, the growth of certain cancers, and the
554:
Schreuder HA, van Berkel WJ, Eppink MH, Bunthol C (1999). "Phe161 and Arg166 variants of p-hydroxybenzoate hydroxylase. Implications for NADPH recognition and structural stability".
345:
and may thereby contribute to limiting there biological effects. (However, the 20-hydroxy metabolite of 12-hydroxyeicosatetraenoic acid proved able to contract coronary arteries.)
397:
919:"Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid"
833:
Sugiura, K; Akiyama, M (2015). "Update on autosomal recessive congenital ichthyosis: MRNA analysis using hair samples is a powerful tool for genetic diagnosis".
139:
also possesses ω hydroxylase activity. These CYP ω-hydroxylases can be categorized into several groups based on their substrates and consequential function
970:; Campbell, W. B. (1996). "Metabolism of arachidonic acid by canine polymorphonuclear leukocytes synthesis of lipoxygenase and omega-oxidized metabolites".
1216:
1109:
1284:
1023:
299:
1461:
1184:
684:
Chuang, S. S.; Helvig, C; Taimi, M; Ramshaw, H. A.; Collop, A. H.; Amad, M; White, J. A.; Petkovich, M; Jones, G; Korczak, B (2004).
1157:
753:
1196:
1142:
736:
Johnson, A. L.; Edson, K. Z.; Totah, R. A.; Rettie, A. E. (2015). "Cytochrome P450 ω-Hydroxylases in
Inflammation and Cancer".
686:"CYP2U1, a novel human thymus- and brain-specific cytochrome P450, catalyzes omega- and (omega-1)-hydroxylation of fatty acids"
385:
349:
330:
798:
Hardwick, J. P. (2008). "Cytochrome P450 omega hydroxylase (CYP4) function in fatty acid metabolism and metabolic diseases".
357:
310:
1001:
381:
317:. This hydroxylation greatly reduces the ability of these arachidonic acid metabolites to stimulate cells that mediate
646:
Kroetz, D. L.; Xu, F (2005). "Regulation and inhibition of arachidonic acid omega-hydroxylases and 20-HETE formation".
1425:
1274:
314:
259:
1016:
206:
also metabolize these fatty acids. Subsequent to their ω-hydroxylation, these products are converted to their acyl
348:
7) CYP4A11, CYP4F2, CYP4F3B, CYP4F11, CYP4F12, CYP4V2, CYP2U1, and possibly CYP4Z1 metabolize arachidonic acid to
1420:
1381:
1371:
1357:
1353:
1343:
1331:
1311:
1294:
1262:
1226:
1126:
1053:
470:"The Functions of Cytochrome P450 ω-hydroxylases and the Associated Eicosanoids in Inflammation-Related Diseases"
1456:
1044:
870:"Metabolism of 5-hydroxyicosatetraenoate by human neutrophils: Production of a novel omega-oxidized derivative"
262:, i.e. fatty acids that are 22 to 26 carbons long. These hydroxyl fatty acids are then serially metabolized by
175:
1266:
1057:
519:
Harayama S, Kok M, Neidle EL (1992). "Functional and evolutionary relationships among diverse oxygenases".
270:, and dicarboxylyl CoA synthetase to form their respective CoA-bound dicarboxylic acids and transferred to
1405:
1321:
1070:
267:
231:
148:
1201:
1174:
1009:
426:
389:
373:
263:
227:
66:
1316:
1279:
1040:
422:
393:
384:, possibly by a 20-HETE-dependent mechanism in a small percentage of patients with this disease (see
1302:
295:
86:
82:
1065:
899:
579:
353:
322:
1211:
1099:
987:
948:
891:
850:
815:
769:
749:
707:
663:
659:
628:
571:
536:
501:
284:
252:
1451:
1446:
979:
938:
930:
881:
842:
807:
759:
741:
697:
655:
618:
610:
563:
528:
491:
481:
418:
1189:
369:
326:
219:
164:
55:
532:
1415:
1395:
1390:
1032:
943:
918:
764:
623:
598:
496:
469:
409:
Cytochrome P450 (CYP) ω-hydroxylases are enzymes that play a role in the metabolism of
306:
215:
160:
567:
89:
agents to regulate various functions such as blood pressure control and inflammation.
1440:
983:
967:
434:
414:
280:
248:
110:
70:
903:
583:
1234:
1230:
846:
318:
276:
244:
211:
156:
69:. The CYP omega hydroxylases are often referred to as monoxygenases; however, the
368:
CYP4F2-dependent 20-HETE production of 20-HETE in the prevention of hypertension,
934:
886:
869:
745:
430:
1366:
811:
614:
486:
410:
271:
239:
235:
78:
74:
63:
738:
Cytochrome P450 Function and
Pharmacological Roles in Inflammation and Cancer
1335:
1298:
1242:
1036:
342:
338:
207:
152:
952:
854:
819:
773:
711:
702:
685:
667:
632:
575:
505:
991:
923:
Biochimica et
Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
895:
540:
1114:
868:
O'Flaherty, J. T.; Wykle, R. L.; Redman, J; Samuel, M; Thomas, M (1986).
59:
364:
CYP4F11-dependent 20-HETE production in the prevention of hypertension;
1410:
334:
291:
258:
4) Members of the CYP4F family, i.e. CYP4F2 and CYP4F3B, ω-hydroxylate
195:
179:
171:
106:
599:"Cytochrome P450-derived eicosanoids: the neglected pathway in cancer"
388:). Some or possibly even all of these CYPs may also omega hydroxylate
1252:
1247:
1206:
400:
but their range of biological activities have yet to be investigated.
203:
199:
191:
187:
183:
144:
136:
1399:
1134:
1092:
1085:
1080:
1075:
972:
Biochimica et
Biophysica Acta (BBA) - Lipids and Lipid Metabolism
1179:
1167:
1162:
1152:
1147:
1130:
1104:
325:
and may thereby limit and contribute to the resolution of these
73:
are CYP450 enzymes that add a hydroxyl group to a wide range of
1005:
329:
reactions. One or more of these CYPs also omega hydroxylate
740:. Advances in Pharmacology. Vol. 74. pp. 223–62.
234:, and dicarboxylyl CoA synthetase to form their respective
597:
Panigrahy D, Kaipainen A, Greene ER, Huang S (Dec 2010).
305:
6) CYP4F2, CYP4F3A, CYP4F3B, and CYP4F11 ω-hydroxylate
396:(DHA). 20-hydroxy EPA and 20-hydroxy-DHA do stimulate
101:[ are reduced to one hydroxyl group and one water (H
58:-containing enzymes that catalyze the addition of a
1380:
1352:
1330:
1293:
1261:
1225:
1125:
1052:
238:(CoA)-bound dicarboxylic acids and transferred to
417:to the ω- or (ω-1)-C atom of substrates such as
398:Peroxisome proliferator-activated receptor alpha
178:, i.e. fatty acids that are 10-16 carbons long;
793:
791:
789:
787:
785:
783:
731:
729:
727:
725:
723:
721:
679:
677:
463:
461:
459:
1017:
386:20-Hydroxyeicosatetraenoic acid#Human studies
8:
648:Annual Review of Pharmacology and Toxicology
105:O molecule) by the concomitant oxidation of
413:and their derivatives. These enzymes add a
143:1) The only member of the CYP4B subfamily,
1024:
1010:
1002:
16:Group of enzymes hydroxylating fatty acids
942:
885:
763:
701:
660:10.1146/annurev.pharmtox.45.120403.100045
622:
495:
485:
455:
300:Congenital ichthyosiform erythroderma
147:, shows a preference for ω-oxidizing
7:
1217:24-hydroxycholesterol 7α-hydroxylase
170:2) A member of the CYP4A subfamily,
533:10.1146/annurev.mi.46.100192.003025
20:Cytochrome P450 omega hydroxylases
14:
917:Powell, W. S.; Rokach, J (2015).
835:Journal of Dermatological Science
1197:Cholesterol 7 alpha-hydroxylase
1143:Flavin-containing monooxygenase
690:Journal of Biological Chemistry
350:20-Hydroxyeicosatetraenoic acid
331:12-hydroxyeicosatetraenoic acid
210:derivatives and transferred to
174:, preferentially ω-hydroxylate
155:derivatives and transferred to
847:10.1016/j.jdermsci.2015.04.009
358:single nucleotide polymorphism
311:5-hydroxyeicosatetraenoic acid
48:cytochrome P450 monooxygenases
24:cytochrome P450 ω-hydroxylases
1:
603:Cancer and Metastasis Reviews
568:10.1016/S0014-5793(98)01726-8
382:Hereditary spastic paraplegia
360:in humans support roles for:
85:agents or on nearby cells as
44:fatty acid omega hydroxylases
984:10.1016/0005-2760(95)00238-3
935:10.1016/j.bbalip.2014.10.008
887:10.4049/jimmunol.137.10.3277
1426:Deoxyhypusine monooxygenase
746:10.1016/bs.apha.2015.05.002
315:5-oxo-eicosatetraenoic acid
260:very long chain fatty acids
1478:
1462:Integral membrane proteins
1421:Ecdysone 20-monooxygenase
1372:Stearoyl-CoA desaturase-1
1344:Dopamine beta-hydroxylase
1312:Phenylalanine hydroxylase
812:10.1016/j.bcp.2008.03.004
615:10.1007/s10555-010-9264-x
487:10.3389/fphar.2021.716801
356:while genetic studies on
214:for complete oxidized by
159:for complete oxidized by
52:fatty acid monooxygenases
28:CYP450 omega hydroxylases
800:Biochemical Pharmacology
176:medium-chain fatty acids
149:short-chain fatty acids
1406:Squalene monooxygenase
1322:Tryptophan hydroxylase
1071:HIF prolyl-hydroxylase
703:10.1074/jbc.M311830200
468:Ni KD, Liu JY (2021).
268:aldehyde dehydrogenase
232:aldehyde dehydrogenase
1202:Methane monooxygenase
1175:Nitric oxide synthase
874:Journal of Immunology
427:eicosapentaenoic acid
405:Clinical significance
390:eicosapentaenoic acid
374:myocardial infarction
264:alcohol dehydrogenase
228:alcohol dehydrogenase
121:+ NADPH + H → ROH + H
36:CYP omega hydroxylase
32:CYP450 ω-hydroxylases
1317:Tyrosine hydroxylase
1041:steroid hydroxylases
521:Annu. Rev. Microbiol
423:docosahexaenoic acid
394:docosahexaenoic acid
1267:iron–sulfur protein
296:Lamellar ichthyosis
87:paracrine signaling
83:autocrine signaling
1066:Prolyl hydroxylase
354:metabolic syndrome
323:allergic reactions
309:and very probably
285:cholesterol esters
253:cholesterol esters
40:CYP ω-hydroxylases
1434:
1433:
1100:Lysyl hydroxylase
441:Future directions
1469:
1026:
1019:
1012:
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996:
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914:
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626:
594:
588:
587:
551:
545:
544:
516:
510:
509:
499:
489:
465:
419:arachidonic acid
1477:
1476:
1472:
1471:
1470:
1468:
1467:
1466:
1457:Cytochrome P450
1437:
1436:
1435:
1430:
1384:- miscellaneous
1376:
1348:
1326:
1289:
1257:
1221:
1212:14α-demethylase
1121:
1048:
1033:Oxidoreductases
1030:
1000:
999:
966:Rosolowsky, M;
965:
964:
960:
916:
915:
911:
880:(10): 3277–83.
867:
866:
862:
832:
831:
827:
806:(12): 2263–75.
797:
796:
781:
756:
735:
734:
719:
683:
682:
675:
645:
644:
640:
596:
595:
591:
553:
552:
548:
518:
517:
513:
474:Front Pharmacol
467:
466:
457:
452:
443:
407:
370:ischemic stroke
327:innate immunity
220:omega oxidation
165:omega oxidation
132:
127:
124:
120:
104:
100:
95:
56:cytochrome P450
54:, are a set of
17:
12:
11:
5:
1475:
1473:
1465:
1464:
1459:
1454:
1449:
1439:
1438:
1432:
1431:
1429:
1428:
1423:
1418:
1413:
1408:
1403:
1396:Heme oxygenase
1393:
1391:Cyclooxygenase
1387:
1385:
1378:
1377:
1375:
1374:
1369:
1363:
1361:
1350:
1349:
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1328:
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1325:
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1277:
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1239:
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1222:
1220:
1219:
1214:
1209:
1204:
1199:
1194:
1193:
1192:
1187:
1182:
1172:
1171:
1170:
1165:
1160:
1155:
1150:
1139:
1137:
1123:
1122:
1120:
1119:
1118:
1117:
1112:
1102:
1097:
1096:
1095:
1090:
1089:
1088:
1083:
1078:
1062:
1060:
1058:2-oxoglutarate
1050:
1049:
1031:
1029:
1028:
1021:
1014:
1006:
998:
997:
958:
909:
860:
825:
779:
754:
717:
696:(8): 6305–14.
673:
638:
589:
562:(3): 251–255.
546:
511:
454:
453:
451:
448:
442:
439:
435:prostaglandins
415:hydroxyl group
406:
403:
402:
401:
346:
307:leukotriene B4
303:
288:
256:
223:
216:beta oxidation
168:
161:beta oxidation
131:
128:
122:
118:
115:
102:
98:
94:
91:
71:monooxygenases
22:, also termed
15:
13:
10:
9:
6:
4:
3:
2:
1474:
1463:
1460:
1458:
1455:
1453:
1450:
1448:
1445:
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1427:
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1337:
1333:
1329:
1323:
1320:
1318:
1315:
1313:
1310:
1309:
1307:
1304:
1303:BH4 dependent
1300:
1296:
1292:
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1281:
1278:
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1273:
1272:
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1027:
1022:
1020:
1015:
1013:
1008:
1007:
1004:
993:
989:
985:
981:
978:(2): 143–50.
977:
973:
969:
962:
959:
954:
950:
945:
940:
936:
932:
929:(4): 340–55.
928:
924:
920:
913:
910:
905:
901:
897:
893:
888:
883:
879:
875:
871:
864:
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766:
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755:9780128031193
751:
747:
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665:
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653:
649:
642:
639:
634:
630:
625:
620:
616:
612:
609:(4): 723–35.
608:
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581:
577:
573:
569:
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561:
557:
550:
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281:triglycerides
278:
277:phospholipids
273:
269:
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250:
249:triglycerides
246:
245:phospholipids
241:
237:
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221:
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209:
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162:
158:
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141:
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138:
129:
126:
114:
112:
111:monooxygenase
108:
92:
90:
88:
84:
80:
76:
72:
68:
65:
62:residue to a
61:
57:
53:
49:
45:
41:
37:
33:
29:
25:
21:
1235:flavoprotein
1039:, including
1037:dioxygenases
975:
971:
968:Falck, J. R.
961:
926:
922:
912:
877:
873:
863:
838:
834:
828:
803:
799:
737:
693:
689:
651:
647:
641:
606:
602:
592:
559:
555:
549:
524:
520:
514:
477:
473:
444:
431:leukotrienes
408:
377:
365:
361:
319:inflammation
212:mitochondria
157:mitochondria
133:
116:
96:
51:
47:
43:
39:
35:
31:
27:
23:
19:
18:
527:: 565–601.
411:fatty acids
298:subtype of
272:peroxisomes
240:peroxisomes
1441:Categories
1367:Tyrosinase
1334:: reduced
1297:: reduced
1265:: reduced
1229:: reduced
841:(1): 4–9.
654:: 413–38.
480:: 716801.
450:References
392:(EPA) and
380:CYP2U1 in
341:, and acyl
339:hepoxilins
302:in humans.
236:Coenzyme A
218:(see also
163:(see also
79:catabolism
75:xenobiotic
64:fatty acid
1336:ascorbate
1299:pteridine
556:FEBS Lett
343:ceramides
208:carnitine
153:carnitine
130:Functions
125:O + NADP
67:substrate
953:25449650
904:41172022
855:25982146
820:18433732
774:26233909
712:14660610
668:15822183
633:20941528
584:21305517
576:10025942
506:34594219
335:lipoxins
60:hydroxyl
1452:EC 1.14
1447:Enzymes
1382:1.14.99
1360:: other
1354:1.14.18
1332:1.14.17
1295:1.14.16
1263:1.14.15
1227:1.14.14
1127:1.14.13
1054:1.14.11
992:8652640
944:5710736
896:3095426
765:4667791
624:2962793
541:1444267
497:8476763
292:CYP4F22
196:CYP4F11
180:CYP4A11
172:CYP4A11
107:NAD(P)H
1231:flavin
1110:ALKBH1
990:
951:
941:
902:
894:
853:
818:
772:
762:
752:
710:
666:
631:
621:
582:
574:
539:
504:
494:
433:, and
376:; and
372:, and
283:, and
251:, and
204:CYP4Z1
202:, and
200:CYP4V2
192:CYP4F3
188:CYP4F3
184:CYP4F2
145:CYP4B1
137:CYP2U1
117:RH + O
93:Action
50:, and
1400:HMOX1
1135:NADPH
1093:P4HTM
1086:EGLN3
1081:EGLN2
1076:EGLN1
1047:1.14)
900:S2CID
580:S2CID
109:(see
1416:21A2
1411:17A1
1285:11A1
1280:11B2
1275:11B1
1243:19A1
1190:NOS3
1185:NOS2
1180:NOS1
1168:FMO5
1163:FMO4
1158:FMO3
1153:FMO2
1148:FMO1
1131:NADH
1105:AlkB
988:PMID
976:1300
949:PMID
927:1851
892:PMID
851:PMID
816:PMID
770:PMID
750:ISBN
708:PMID
664:PMID
629:PMID
572:PMID
537:PMID
502:PMID
321:and
313:and
194:B,
1253:2E1
1248:2D6
1233:or
1207:3A4
1133:or
1115:FTO
980:doi
939:PMC
931:doi
882:doi
878:137
843:doi
808:doi
760:PMC
742:doi
698:doi
694:279
656:doi
619:PMC
611:doi
564:doi
560:443
529:doi
492:PMC
482:doi
290:5)
190:A,
113:).
1443::
1358:19
1129::
1056::
1045:EC
1035::
986:.
974:.
947:.
937:.
925:.
921:.
898:.
890:.
876:.
872:.
849:.
839:79
837:.
814:.
804:75
802:.
782:^
768:.
758:.
748:.
720:^
706:.
692:.
688:.
676:^
662:.
652:45
650:.
627:.
617:.
607:29
605:.
601:.
578:.
570:.
558:.
535:.
525:46
523:.
500:.
490:.
478:12
476:.
472:.
458:^
429:,
425:,
421:,
378:c)
366:b)
362:a)
337:,
333:,
279:,
266:,
247:,
230:,
222:).
198:,
186:,
182:,
167:).
46:,
42:,
38:,
34:,
30:,
26:,
1402:)
1398:(
1356:-
1305:)
1301:(
1043:(
1025:e
1018:t
1011:v
994:.
982::
955:.
933::
906:.
884::
857:.
845::
822:.
810::
776:.
744::
714:.
700::
670:.
658::
635:.
613::
586:.
566::
543:.
531::
508:.
484::
287:.
255:.
123:2
119:2
103:2
99:2
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