57e94b4b0e889d72cc40ca905bf0239d pmc_29143802.pdf d4997a453be96d1427cd06b0529f550388c37855 pmc_29143802.pdf e8a6d7ccf024e10002addf7ed532799d6ccb14a7f206f931ad53be50c8673657 pmc_29143802.pdf Title: The Inhibitory Effects of Cobalt Protoporphyrin IX and Cannabinoid 2 Receptor Agonists in Type 2 Diabetic Mice Subject: The activation of the transcription factor Nrf2 inhibits neuropathy and modulates the activity of delta-opioid receptors (DOR) in type 2 diabetic mice but the impact of Nrf2/HO-1 pathway on the antinociceptive actions of cannabinoid 2 receptors (CB2R) has not been assessed. Using male mice BKS.Cg-m+/+Leprdb/J (db/db) we investigated if treatment with cobalt protoporphyrin IX (CoPP), an HO-1 inductor, inhibited mechanical allodynia, hyperglycemia and obesity associated to type 2 diabetes. The antinociceptive effects of JWH-015 and JWH-133 (CB2R agonists) administered with and without CoPP or sulforaphane (SFN), a Nrf2 transcription factor activator, have been also evaluated. The expression of Nrf2, HO-1, NAD(P)H: quinone oxidoreductase 1 (NQO1) and c-Jun N-terminal kinase (JNK) in sciatic nerve and that of the CB2R on the dorsal root ganglia from animals treated with CoPP and/or SFN were assessed. CoPP treatment inhibited allodynia, hyperglycemia and body weight gain in db/db mice by enhancing HO-1/NQO1 levels and reducing JNK phosphorylation. Both CoPP and SFN improved the antiallodynic effects of JWH-015 and JWH-133 and expression of CB2R in db/db mice. Therefore, we concluded that the activation of antioxidant Nrf2/HO-1 pathway potentiate the effects of CB2R agonists and might be suitable for the treatment of painful neuropathy linked to type 2 diabetes. Keywords: antinociception; cannabinoid receptors; diabetic neuropathy; heme oxygenase 1; NAD(P)H: quinone oxidoreductase 1; Nrf2 transcription factor Author: Christina McDonnell, Sergi Leánez and Olga Pol Creator: LaTeX with hyperref package Producer: pdfTeX-1.40.17 CreationDate: Sat Oct 28 10:23:08 2017 CEST ModDate: Sat Oct 28 10:23:08 2017 CEST Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 13 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 2773214 bytes Optimized: no PDF version: 1.5 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- XZXPAH+URWPalladioL-Ital Type 1 Custom yes yes no 98 0 OBEMTN+URWPalladioL-Bold Type 1 Custom yes yes no 99 0 AIQCCL+VnURWPalladioL-Bold Type 1 Custom yes yes no 100 0 OXBKYU+TeXGyreAdventor-Bold Type 1 Custom yes yes no 101 0 IUCFSL+URWPalladioL-Roma Type 1 Custom yes yes no 102 0 MWHIBA+VnURWPalladioL Type 1 Custom yes yes no 103 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 108 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 109 0 OJYQXC+CMSY10 Type 1 Builtin yes yes no 153 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 179 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 180 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 181 0 Times New Roman TrueType WinAnsi no no no 182 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 199 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 200 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 201 0 Times New Roman TrueType WinAnsi no no no 202 0 IHZXYI+EURM10 Type 1 Builtin yes yes no 229 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 232 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 233 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 234 0 Times New Roman TrueType WinAnsi no no no 235 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 260 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 261 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 262 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 263 0 Times New Roman TrueType WinAnsi no no no 264 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 293 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 294 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 295 0 Times New Roman TrueType WinAnsi no no no 296 0 ABCDEE+Palatino Linotype TrueType WinAnsi yes yes no 338 0 ABCDEE+Palatino Linotype,Italic TrueType WinAnsi yes yes no 339 0 ABCDEE+Palatino Linotype,Bold TrueType WinAnsi yes yes no 340 0 ABCDEE+Palatino Linotype CID TrueType Identity-H yes yes yes 341 0 Times New Roman TrueType WinAnsi no no no 342 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-02-08 02:44:39 CET RepresentationInformation: pmc_29143802.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2018-02-08 07:41:47 CET Size: 2773214 Format: PDF Version: 1.5 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 0 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: ぉのぴひはつふっぴどはの〠 Item: Title: げづびふぬぴび〠 Children: Item: Title: いどちぢづぴどっ〠ぎづふひはばちぴとべ〠 Item: Title: ぅててづっぴび〠はて〠ぃはぐぐ〠はの〠きづっとちのどっちぬ〠ぁぬぬはつべのどち〠 Item: Title: ぅててづっぴび〠はて〠ぃはぐぐ〠はの〠あぬははつ〠ぇぬふっはびづ〠がづぶづぬび〠ちのつ〠あはつべ〠しづどでとぴ〠 Item: Title: ぅててづっぴび〠はて〠ぃはぐぐ〠はの〠ぎひて〲〬〠えく〭〱〬〠ぎけく〱〠ちのつ〠おぎか〠ぅへばひづびびどはの〠どの〠こっどちぴどっ〠ぎづひぶづ〠 Item: Title: ぅててづっぴび〠はて〠おしえ〭〰〱〵〠ちのつ〠おしえ〭〱〳〳〠はの〠ぴとづ〠きづっとちのどっちぬ〠ぁぬぬはつべのどち〠 Item: Title: ぅててづっぴび〠はて〠ぃはぐぐ〠ちのつ〠こうぎ〠ごひづちぴねづのぴび〠はの〠ぴとづ〠ぁのぴどちぬぬはつべのどっ〠ぅててづっぴび〠はて〠おしえ〭〰〱〵〠ちのつ〠おしえ〭〱〳〳〠 Item: Title: ぅててづっぴび〠はて〠ぃはぐぐ〠ちのつ〠こうぎ〠ごひづちぴねづのぴび〠はの〠ぃあ〲げ〠がづぶづぬび〠どの〠ぴとづ〠いはひびちぬ〠げははぴ〠ぇちのでぬどち〠はて〠つぢ〯つぢ〠きどっづ〠 Item: Title: いどびっふびびどはの〠 Item: Title: きちぴづひどちぬ〠ちのつ〠きづぴとはつび〠 Children: Item: Title: ぁのどねちぬび〠 Item: Title: ぎはっどっづばぴどぶづ〠あづとちぶどはひちぬ〠ごづびぴ〠 Item: Title: しづびぴづひの〠あぬはぴ〠ぁのちぬべびどび〠 Item: Title: ぅへばづひどねづのぴちぬ〠ぐひはっづつふひづ〠 Item: Title: いひふでび〠 Item: Title: こぴちぴどびぴどっちぬ〠ぁのちぬべびどび〠 Filters: FilterPipeline: FlateDecode Fonts: Type1: Font: BaseFont: XZXPAH+URWPalladioL-Ital FontSubset: true FirstChar: 3 LastChar: 121 FontDescriptor: FontName: XZXPAH+URWPalladioL-Ital Flags: Symbolic FontBBox: -170, -305, 1010, 941 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: OBEMTN+URWPalladioL-Bold FontSubset: true FirstChar: 3 LastChar: 122 FontDescriptor: FontName: OBEMTN+URWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: AIQCCL+VnURWPalladioL-Bold FontSubset: true FirstChar: 161 LastChar: 161 FontDescriptor: FontName: AIQCCL+VnURWPalladioL-Bold Flags: Symbolic FontBBox: -152, -301, 1000, 935 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: OXBKYU+TeXGyreAdventor-Bold FontSubset: true FirstChar: 68 LastChar: 73 FontDescriptor: FontName: OXBKYU+TeXGyreAdventor-Bold Flags: Symbolic FontBBox: -679, -304, 1661, 1236 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: IHZXYI+EURM10 FontSubset: true FirstChar: 12 LastChar: 22 FontDescriptor: FontName: IHZXYI+EURM10 Flags: Symbolic FontBBox: -32, -243, 1060, 720 FontFile: true Font: BaseFont: IUCFSL+URWPalladioL-Roma FontSubset: true FirstChar: 2 LastChar: 174 FontDescriptor: FontName: IUCFSL+URWPalladioL-Roma Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: MWHIBA+VnURWPalladioL FontSubset: true FirstChar: 161 LastChar: 226 FontDescriptor: FontName: MWHIBA+VnURWPalladioL Flags: Symbolic FontBBox: -166, -283, 1021, 943 FontFile: true EncodingDictionary: Differences: true Font: BaseFont: OJYQXC+CMSY10 FontSubset: true FirstChar: 0 LastChar: 14 FontDescriptor: FontName: OJYQXC+CMSY10 Flags: Symbolic FontBBox: -29, -960, 1116, 775 FontFile: true Pages: Page: Sequence: 1 Annotations: Annotation: Subtype: Link Rect: 75, 757, 221, 793 Annotation: Subtype: Link Rect: 474, 757, 519, 793 Annotation: Subtype: Link Rect: 347, 641, 360, 656 Annotation: Subtype: Link Rect: 107, 236, 114, 244 ActionDest: 444 Annotation: Subtype: Link Rect: 156, 222, 163, 231 ActionDest: 444 Annotation: Subtype: Link Rect: 223, 208, 230, 217 ActionDest: 444 Annotation: Subtype: Link Rect: 117, 154, 124, 163 ActionDest: 444 Annotation: Subtype: Link Rect: 125, 154, 131, 163 ActionDest: 444 Annotation: Subtype: Link Rect: 294, 141, 301, 150 ActionDest: 444 Annotation: Subtype: Link Rect: 403, 127, 410, 136 ActionDest: 444 Annotation: Subtype: Link Rect: 101, 100, 108, 109 ActionDest: 444 Annotation: Subtype: Link Rect: 111, 100, 123, 109 ActionDest: 444 Annotation: Subtype: Link Rect: 365, 100, 377, 109 ActionDest: 490 Annotation: Subtype: Link Rect: 193, 38, 272, 50 Annotation: Subtype: Link Rect: 411, 38, 519, 50 Page: Sequence: 2 Annotations: Annotation: Subtype: Link Rect: 123, 702, 135, 711 ActionDest: 490 Annotation: Subtype: Link Rect: 135, 702, 147, 711 ActionDest: 490 Annotation: Subtype: Link Rect: 323, 661, 335, 670 ActionDest: 490 Annotation: Subtype: Link Rect: 127, 634, 139, 643 ActionDest: 490 Annotation: Subtype: Link Rect: 140, 634, 152, 643 ActionDest: 490 Annotation: Subtype: Link Rect: 188, 607, 200, 616 ActionDest: 490 Annotation: Subtype: Link Rect: 200, 607, 212, 616 ActionDest: 490 Annotation: Subtype: Link Rect: 491, 594, 503, 603 ActionDest: 490 Annotation: Subtype: Link Rect: 503, 594, 515, 603 ActionDest: 490 Annotation: Subtype: Link Rect: 339, 526, 351, 535 ActionDest: 490 Annotation: Subtype: Link Rect: 335, 499, 347, 508 ActionDest: 490 Annotation: Subtype: Link Rect: 347, 499, 359, 508 ActionDest: 490 Annotation: Subtype: Link Rect: 315, 445, 327, 454 ActionDest: 490 Annotation: Subtype: Link Rect: 404, 391, 416, 400 ActionDest: 490 Annotation: Subtype: Link Rect: 416, 391, 428, 400 ActionDest: 490 Annotation: Subtype: Link Rect: 429, 391, 441, 400 ActionDest: 490 Annotation: Subtype: Link Rect: 337, 145, 344, 157 ActionDest: 172 Page: Sequence: 3 Annotations: Annotation: Subtype: Link Rect: 481, 720, 488, 732 ActionDest: 172 Annotation: Subtype: Link Rect: 171, 707, 178, 719 ActionDest: 172 Page: Sequence: 4 Annotations: Annotation: Subtype: Link Rect: 175, 643, 182, 655 ActionDest: 224 Annotation: Subtype: Link Rect: 146, 629, 153, 641 ActionDest: 224 Annotation: Subtype: Link Rect: 110, 575, 117, 587 ActionDest: 224 Annotation: Subtype: Link Rect: 419, 562, 426, 574 ActionDest: 224 Page: Sequence: 5 Annotations: Annotation: Subtype: Link Rect: 332, 720, 339, 732 ActionDest: 252 Annotation: Subtype: Link Rect: 308, 294, 315, 306 ActionDest: 252 Annotation: Subtype: Link Rect: 130, 82, 137, 94 ActionDest: 287 Page: Sequence: 6 Annotations: Annotation: Subtype: Link Rect: 495, 199, 502, 211 ActionDest: 331 Page: Sequence: 7 Annotations: Annotation: Subtype: Link Rect: 364, 292, 371, 301 ActionDest: 444 Annotation: Subtype: Link Rect: 372, 292, 384, 301 ActionDest: 490 Annotation: Subtype: Link Rect: 384, 292, 396, 301 ActionDest: 490 Annotation: Subtype: Link Rect: 116, 278, 128, 287 ActionDest: 490 Annotation: Subtype: Link Rect: 128, 278, 140, 287 ActionDest: 490 Annotation: Subtype: Link Rect: 316, 238, 328, 247 ActionDest: 490 Annotation: Subtype: Link Rect: 329, 238, 341, 247 ActionDest: 490 Annotation: Subtype: Link Rect: 200, 170, 212, 179 ActionDest: 490 Annotation: Subtype: Link Rect: 215, 170, 227, 179 ActionDest: 522 Annotation: Subtype: Link Rect: 356, 143, 363, 152 ActionDest: 444 Annotation: Subtype: Link Rect: 268, 116, 280, 125 ActionDest: 522 Annotation: Subtype: Link Rect: 280, 116, 292, 125 ActionDest: 522 Annotation: Subtype: Link Rect: 426, 76, 438, 85 ActionDest: 490 Annotation: Subtype: Link Rect: 439, 76, 451, 85 ActionDest: 522 Annotation: Subtype: Link Rect: 451, 76, 463, 85 ActionDest: 522 Page: Sequence: 8 Annotations: Annotation: Subtype: Link Rect: 373, 742, 385, 751 ActionDest: 490 Annotation: Subtype: Link Rect: 488, 729, 495, 738 ActionDest: 444 Annotation: Subtype: Link Rect: 495, 729, 502, 738 ActionDest: 444 Annotation: Subtype: Link Rect: 503, 729, 515, 738 ActionDest: 490 Annotation: Subtype: Link Rect: 487, 661, 499, 670 ActionDest: 522 Annotation: Subtype: Link Rect: 166, 634, 178, 643 ActionDest: 490 Annotation: Subtype: Link Rect: 232, 621, 244, 630 ActionDest: 490 Annotation: Subtype: Link Rect: 244, 621, 256, 630 ActionDest: 490 Annotation: Subtype: Link Rect: 490, 513, 502, 522 ActionDest: 490 Annotation: Subtype: Link Rect: 503, 513, 515, 522 ActionDest: 522 Annotation: Subtype: Link Rect: 118, 472, 130, 481 ActionDest: 490 Annotation: Subtype: Link Rect: 130, 472, 142, 481 ActionDest: 490 Annotation: Subtype: Link Rect: 143, 472, 155, 481 ActionDest: 490 Annotation: Subtype: Link Rect: 202, 445, 214, 454 ActionDest: 522 Annotation: Subtype: Link Rect: 451, 445, 463, 454 ActionDest: 490 Annotation: Subtype: Link Rect: 119, 378, 131, 387 ActionDest: 490 Annotation: Subtype: Link Rect: 131, 378, 143, 387 ActionDest: 522 Annotation: Subtype: Link Rect: 144, 378, 156, 387 ActionDest: 522 Annotation: Subtype: Link Rect: 190, 351, 202, 360 ActionDest: 490 Annotation: Subtype: Link Rect: 205, 351, 217, 360 ActionDest: 490 Annotation: Subtype: Link Rect: 217, 351, 229, 360 ActionDest: 522 Annotation: Subtype: Link Rect: 452, 243, 464, 252 ActionDest: 522 Annotation: Subtype: Link Rect: 267, 161, 279, 171 ActionDest: 490 Annotation: Subtype: Link Rect: 446, 148, 458, 157 ActionDest: 490 Annotation: Subtype: Link Rect: 458, 148, 470, 157 ActionDest: 522 Page: Sequence: 9 Annotations: Annotation: Subtype: Link Rect: 371, 499, 383, 508 ActionDest: 490 Annotation: Subtype: Link Rect: 384, 499, 396, 508 ActionDest: 490 Annotation: Subtype: Link Rect: 443, 458, 455, 467 ActionDest: 522 Page: Sequence: 10 Annotations: Annotation: Subtype: Link Rect: 499, 375, 511, 385 ActionDest: 490 Annotation: Subtype: Link Rect: 393, 238, 400, 247 ActionDest: 444 Annotation: Subtype: Link Rect: 401, 238, 413, 247 ActionDest: 490 Annotation: Subtype: Link Rect: 413, 238, 425, 247 ActionDest: 490 Annotation: Subtype: Link Rect: 188, 184, 195, 193 ActionDest: 444 Annotation: Subtype: Link Rect: 195, 184, 207, 193 ActionDest: 490 Annotation: Subtype: Link Rect: 208, 184, 220, 193 ActionDest: 490 Page: Sequence: 11 Annotations: Annotation: Subtype: Link Rect: 324, 397, 361, 407 Annotation: Subtype: Link Rect: 259, 371, 296, 381 Annotation: Subtype: Link Rect: 302, 371, 338, 381 Annotation: Subtype: Link Rect: 478, 357, 516, 368 Annotation: Subtype: Link Rect: 100, 345, 136, 355 Annotation: Subtype: Link Rect: 224, 319, 262, 329 Annotation: Subtype: Link Rect: 268, 319, 304, 329 Annotation: Subtype: Link Rect: 336, 292, 374, 303 Annotation: Subtype: Link Rect: 380, 292, 416, 303 Annotation: Subtype: Link Rect: 478, 267, 516, 278 Annotation: Subtype: Link Rect: 100, 255, 136, 265 Annotation: Subtype: Link Rect: 480, 228, 516, 239 Annotation: Subtype: Link Rect: 100, 216, 136, 226 Annotation: Subtype: Link Rect: 340, 176, 377, 187 Annotation: Subtype: Link Rect: 384, 176, 420, 187 Annotation: Subtype: Link Rect: 100, 138, 137, 148 Annotation: Subtype: Link Rect: 143, 138, 179, 148 Annotation: Subtype: Link Rect: 135, 100, 173, 110 Annotation: Subtype: Link Rect: 179, 100, 215, 110 Page: Sequence: 12 Annotations: Annotation: Subtype: Link Rect: 140, 715, 178, 725 Annotation: Subtype: Link Rect: 184, 715, 220, 725 Annotation: Subtype: Link Rect: 405, 688, 442, 699 Annotation: Subtype: Link Rect: 448, 688, 484, 699 Annotation: Subtype: Link Rect: 145, 651, 182, 661 Annotation: Subtype: Link Rect: 189, 651, 225, 661 Annotation: Subtype: Link Rect: 100, 612, 137, 622 Annotation: Subtype: Link Rect: 143, 612, 179, 622 Annotation: Subtype: Link Rect: 331, 585, 369, 596 Annotation: Subtype: Link Rect: 375, 585, 411, 596 Annotation: Subtype: Link Rect: 220, 547, 258, 557 Annotation: Subtype: Link Rect: 264, 547, 300, 557 Annotation: Subtype: Link Rect: 479, 533, 516, 544 Annotation: Subtype: Link Rect: 100, 521, 136, 532 Annotation: Subtype: Link Rect: 100, 496, 137, 506 Annotation: Subtype: Link Rect: 143, 496, 179, 506 Annotation: Subtype: Link Rect: 385, 469, 423, 480 Annotation: Subtype: Link Rect: 429, 469, 465, 480 Annotation: Subtype: Link Rect: 416, 443, 454, 454 Annotation: Subtype: Link Rect: 460, 443, 496, 454 Annotation: Subtype: Link Rect: 163, 405, 200, 415 Annotation: Subtype: Link Rect: 206, 405, 242, 415 Annotation: Subtype: Link Rect: 375, 378, 412, 390 Annotation: Subtype: Link Rect: 418, 378, 454, 390 Annotation: Subtype: Link Rect: 136, 341, 173, 351 Annotation: Subtype: Link Rect: 180, 341, 216, 351 Annotation: Subtype: Link Rect: 208, 301, 245, 312 Annotation: Subtype: Link Rect: 252, 301, 288, 312 Annotation: Subtype: Link Rect: 479, 262, 516, 273 Annotation: Subtype: Link Rect: 100, 250, 136, 260 Annotation: Subtype: Link Rect: 422, 224, 460, 235 Annotation: Subtype: Link Rect: 466, 224, 502, 235 Annotation: Subtype: Link Rect: 268, 185, 306, 196 Annotation: Subtype: Link Rect: 312, 185, 348, 196 Annotation: Subtype: Link Rect: 255, 134, 293, 144 Annotation: Subtype: Link Rect: 299, 134, 335, 144 Annotation: Subtype: Link Rect: 145, 95, 182, 105 Annotation: Subtype: Link Rect: 189, 95, 225, 105 Page: Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 163, 715, 200, 725 Annotation: Subtype: Link Rect: 206, 715, 242, 725 Annotation: Subtype: Link Rect: 145, 676, 182, 686 Annotation: Subtype: Link Rect: 189, 676, 225, 686 Annotation: Subtype: Link Rect: 353, 637, 390, 648 Annotation: Subtype: Link Rect: 397, 637, 433, 648 Annotation: Subtype: Link Rect: 480, 611, 516, 622 Annotation: Subtype: Link Rect: 100, 599, 136, 609 Annotation: Subtype: Link Rect: 249, 572, 285, 583 Annotation: Subtype: Link Rect: 216, 534, 254, 544 Annotation: Subtype: Link Rect: 260, 534, 296, 544 Annotation: Subtype: Link Rect: 136, 508, 173, 519 Annotation: Subtype: Link Rect: 180, 508, 216, 519 Annotation: Subtype: Link Rect: 242, 482, 280, 493 Annotation: Subtype: Link Rect: 286, 482, 322, 493 Annotation: Subtype: Link Rect: 401, 443, 439, 454 Annotation: Subtype: Link Rect: 445, 443, 481, 454 Annotation: Subtype: Link Rect: 312, 404, 349, 415 Annotation: Subtype: Link Rect: 355, 404, 391, 415 Annotation: Subtype: Link Rect: 310, 378, 347, 390 Annotation: Subtype: Link Rect: 354, 378, 390, 390 Annotation: Subtype: Link Rect: 312, 353, 350, 364 Annotation: Subtype: Link Rect: 356, 353, 392, 364 Annotation: Subtype: Link Rect: 100, 315, 137, 325 Annotation: Subtype: Link Rect: 143, 315, 179, 325 Annotation: Subtype: Link Rect: 305, 288, 343, 299 Annotation: Subtype: Link Rect: 76, 246, 166, 277 Annotation: Subtype: Link Rect: 234, 240, 424, 251 Checksum: f4815226 Type: CRC32 Checksum: 57e94b4b0e889d72cc40ca905bf0239d Type: MD5 Checksum: d4997a453be96d1427cd06b0529f550388c37855 Type: SHA-1 Checksum: e8a6d7ccf024e10002addf7ed532799d6ccb14a7f206f931ad53be50c8673657 Type: SHA-256