PublicNotices.Eu Michael R. Graham Research Article Received:1 August 2014 Revised:8 August 2014 PublicNotices.Eu Accepted:9 August 2014 Published online in publicnotices.eu interscience (www.publicnotices.eu) DOI: 01.2014/pn.eu.12 Boxing Landmark Travesty of Justice We should not be allowed to break the law, or pervert the course of justice, because we have the power. This is misfeasance and malfeasance and must be brought to justice. The following article highlights the dangers of drug abuse but also the extent to which the authorities will stoop to achieve what they “believe” is the moral high ground. PublicNotices.Eu Michael R. Graham What Price is “Roid” Rage? Michael R. Graham,∗1 Counterfeiting in drugs such as anabolic-androgenic steroids (AAS) is increasing exponentially and pervading all aspects of sport, especially combat sports such as boxing. They are still the most widely abused drugs in all aspects of sport. However, less detectable drugs such as the drugs of abuse, particularly human growth hormone (h-GH), and insulin-like growth factor 1 Long arm 3 (IgF-1 LR3) has resulted in increased importation not only for performance enhancement in sport, but also for personal use. The substantial increase in this market has opened up avenues for counterfeiting, estimated as a multi-million pound business. There are, however, substantial health risks adverse effects from possible contaminated vials, manufactured in non-sterile environments, which may result in a variety of pathologies and communicable diseases, such as Hepatitis C and Human Immuno-deficiency virus. Despite being legal outside sport, as recreational drugs of abuse, there can be catastrophic effects on sports persons’ legitimate status in both amateur and professional sport. The recent landmark case resulting in UKAD’s life-time ban of a non-competitive father’s association with sport and his daughter’s four year ban from boxing, because of alleged knowledge and complicity in trafficking, indicates the extent to which the anti-doping authorities will stamp their power to prevent drug abuse within the world of sport. In 2009, in the UK, a study of samples by a World Anti-Doping Agency (WADA) accredited laboratory, obtained from the underground market resulted in the analysis of parenteral samples and oral samples and identified fifty-three per cent of the injectable AAS esters and 21% of the oral tablets were counterfeit. Culture and sensitivity revealed the presence of commensal organisms, which can contribute to the development of communicable diseases. The retail price of these drugs on the internet and black market is freely available, but the trade prices are implausibly economical because of the profitability of the manufacture of these products in countries such as China, Colombia, Egypt, Greece, India, Mexico, Pakistan, Romania, Russia, Thailand and Turkey. Users of AAS, hGH and IgF-1 LR3 for sports such as boxing are paying prices which may risk not only their health because of below par meticulous manufacture of such products, but also any future potential rewards they may have had because of natural success in sport. Key words: AAS, counterfeiting; communicable diseases; h-GH; IgF-1 LR3 Correspondence to: *1.Michael R. Graham, Llantarnam Health Care, Parc-y-Bont, Newport Road, Llantarnam, Cwmbran, Torfaen, NP44 3AF, E-mail: [email protected]; [email protected]; PublicNotices.Eu Michael R. Graham Introduction On 06.05.2014 The National Anti-Doping Panel (NADP) Tribunal issued a life ban to the father of an amateur female boxer, for a conviction of exchange of anabolic-androgenic steroids (AAS). Despite the prosecution wanting an eight year ban, the Tribunal also issued a four year ban to the daughter on the following allegations: Under section 1.5 and 1.6 of the United Kingdom Anti-Doping (UKAD) Regulations (Appendix 1). Regulation 1.5 stipulates that at all relevant times, she was a licensed member of the WABA and bound by its Anti-Doping Rules. Regulation 1.6 stipulates: The following constitute Anti-Doping Violations contrary to Article 2 of the UKAD Rules: 1.6.1 (in the case of an Athlete) Possession of one or more Prohibited Substances (UKAD Rules - Article 2.6.1); 1.6.2 (in the case of an Athlete Support Personnel) Possession of one or more Prohibited Substances (UKAD Rules - Article 2.6.3); 1.6.3 Trafficking or Attempting Trafficking in any Prohibited Substance (UKAD Rules Article 2.7); and 1.6.4 Assisting, encouraging, aiding, abetting or covering up or any other type of complicity involving an anti-doping rule violation or any attempted anti-doping rule violation (UKAD Rules - Article 2.8). An appeal was launched. The Tribunal had consisted of a Queen’s Council (QC), who chaired the tribunal and two untrained, unqualified panel members who were able to interpret anti-doping laws or legal facts in the index case. They were both Olympic athletes and one was a general medical practitioner. The defence believed that the ruling against the amateur boxer was unjust and unfair, on the following grounds: Abuse of process; Misrepresentation of the facts; Misdirection of the facts by the Chairman to unqualified and untrained panel members. No evidence was adduced at the hearing by any of the witnesses that linked the amateur boxer to any drug involvement whatsoever. The evidence that was adduced by the witnesses acquitted the amateur boxer of any and all knowledge and complicity in her father’s activity. She had no “mens rea” of her father’s activity and no “actus reus” in her father’s activity. She had been proven to have a negative drug test, complying with the NADP/UKAD specifications for sport. The Chairman, who was legally qualified to interpret the facts, misdirected the unqualified and untrained panel members to a level that confused their memories as to what was stated on examination and cross-examination. They did not all sign the ruling. On the balance of probabilities there was no evidence linking her to wrong doing, nor complicity in her father’s activity. The cases that were referred to in the disclosure prior to this tribunal and the subsequent judgement had no bearing on the index case and were totally irrelevant. They referred to individuals who had pleaded guilt to unlawful dealings in WADA banned substances and who had tested positive to WADA banned substances. Despite having a clean enhanced criminal records bureau (CRB) check and a negative drug’s test, the NADP Tribunal also dismissed an appeal, on 30.07.2014.[1]. On this occasion there were two QCs and one retired doctor, who was not licenced to practice medicine in the UK and had no training or qualifications in anti-doping laws or legal facts in the index case [Appendix 2]. PublicNotices.Eu Michael R. Graham Yearly reports from the World Anti-Doping Agency (WADA) identify that AAS are still the most abused group of drugs in competitive sport, despite severe penalties for positive test results. However multiple countries license the sale of AAS without a medical prescription [2], [3]. and sale of these products to overseas customers is also not restricted neither directly nor through snail mail and the internet. Most AAS found in Europe are initiated from countries within the European Union and Russia but also from Thailand, Turkey, Egypt, India and Pakistan [3]. In the US, significant quantities of AAS emanate from Mexico, as well as from Russia, Romania, and Greece [2]. In the UK, performance enhancing drugs are controlled under Schedule 4, Part 2 of the Misuse of Drugs Act 1971. There is an exemption from restriction on the possession of these substances, when they are in a medicinal product and are for self-administration. AAS can only be obtained in the UK for non-medical use from sources of unknown derivation, such as the black market or the internet. These products will definitely not be manufactured in accordance with good practice. There has been an enormous increase by female athletes leading to an assessment of the type of drugs they use [4] [5]. Past doping violations, contravening the WADA code, illustrate the excessive ‘‘polypharmacy’’ in the athletic world have [6] have identified extensive doping regimes of famous household named athletes such as Dwain Chambers, in athletics [8] and more recently Lamont Peterson, in boxing, when he tested positive for Testosterone in his world title victory over Amir Khan [9]. The use of performance-enhancing drugs (PED) is contrary to all Olympic values and creates negative role models for young athletes. Peer influence and the information that AAS administered by intra-muscular (IM) injection are ‘less harmful’ than oral products has increased the use of IM preparations. The escalation in the frequency of IM abscesses in a cohorts of sportspersons has been considered to be as a result of the use of non-sterilised or contaminated counterfeit products obtained from the black market. Such harm to health has a gargantuan price and that price is paid in cash for black market products and is resulting in lengthy bans for any complicity in any illegal dealing in every aspect of sport [1], [9]. Methods Ethical approval for this study was granted by Llantarnam Advocacy Services. Discussions with AAS users provided new counterfeit companies which are selling AAS products online. The generic name of the drug was identified from the brand name, specified on the label. All vials were analysed for culture and sensitivity (C & S) prior to analysis for chemical formulaic content. Gas chromatography-mass spectrometry conditions Gas chromatography-mass spectrometry (GC–MS) analysis was carried out on an Agilent 5973 mass selective detector coupled to an Agilent 6890 GC system with an Agilent 7683 autosampler. The GC was fitted with a cross-linked polymethylsiloxane capillary column (HP-1; length 25 m; internal diameter 0.2 mm; film thickness 0.11 µm). The initial column temperature was 180 ◦C for 1 min; this was ramped to 220 ◦Cat8◦C/min, then from 220 to 250 ◦Cat3◦C/min and from 250 to 320 ◦Cat14◦C/min. The final temperature, 320 ◦C, was held for 5 min. Injections (1 µL) were made in the splitless mode; the injection port and transfer line temperatures were 250 and 280 ◦C, respectively. Helium was used as the carrier gas and the flow rate was 0.7 mL/min. For screening purposes, the mass spectrometer was operated in the selected ion monitoring mode (SIM) using an ion specific for the mono or bistrimethylsilyl (TMS) derivative for each compound. Full scan analysis (mass range m/z 80– PublicNotices.Eu Michael R. Graham 650) was used for identification of the compounds detected. The chromatographic conditions are described above. LC-MS/MS analysis A tablet from a bag labelled ‘levothyroxine’ was placed into a tube containing 10 mL of methanol. The contents were mixed thoroughly by sonication and centrifuged at 1320 g for 5 min. Then 0.8 mL of the supernatant was taken and diluted to 5 mL with methanol : water containing 0.1% formic acid (70 : 30). A solution containing 1 µg/mL of thyroxine was prepared in methanol : water containing 0.1% formic acid (70 : 30). A portion of these solution was transferred to autosampler vials and analysed by LC-MS/MS. Chromatographic separation was performed on an Waters Acquity UPLC system using a Zorbax Eclipse XDBC18 column (50 2.1 mm, 1.8 µm particle size) heated to 35 ◦C. The mobile phase×consisted of 0.1% formic acid (v/v) (solvent A) and methanol containing 0.1%formic acid (v/v) (solvent B). A gradient was employed starting at 30% B, increasing to 55% B in 2 min and to 75% B in 8.66 min and returned to the initial conditions in 9.3 min and allowed to equilibrated for a further 0.7 min. The flow rate was 0.25 mL/min. The injection volume was 10 µL. This was coupled to an Applied Biosystems API 3200 triple quadrupole mass spectrometer with a Turbo Ionspray source operating in the positive ion mode. The optimized source conditions were source heater probe temperature 500 ◦C, Turbo Ionspray voltage 5500 V, curtain gas setting of 15 psi, collision gas setting of 6, ion source gas 1 setting of 45 psi, ion source gas 2 setting of 50 psi, declustering potential of 65 V, entrance potential of 10 V, cell exit potential of 51 V, and collision energy of 35 V. The mass spectrometric method was set up to detect the ions (mass range m/z 500–780) produced by after collision induced dissociation of m/z 777.2, the protonated molecule [M+H]+,(product ion scan). The tablet extract gave a peak consistent with the retention times (4.68 min) and product ion spectrum for thyroxine. The protonated molecule was visible at m/z 777 and collision induced dissociation resulted in the formation of m/z 731, 634 and 605 are consistent with those reported previously [10]. Analysis of products A statistical sign test was applied to Tables 1 to 3. Analysis of IM AAS PED vials and Products (Table 2) The contents were transferred to glass vials and a 200 µL portion of each was taken and added to 10 mL of methanol in 20 mL tubes. The contents were mixed thoroughly and then centrifuged at 1320 g for 5 min. Methanol extracts (200 µL) were taken and the solvent was evaporated to dryness under nitrogen at 60 ◦C. The residues were derivatised to form trimethylsilyl derivatives and analysed by full-scan GC-MS, as described above. Steroids in which the tri-ene-one system is present, such as trenbolone acetate and tetrahydrogestrinone, do not derivatise well with the above procedure and a repeat analysis was performed using a different derivatising technique to form a stable methyloxime trimethylsilyl derivative. Methanolic extracts (50 µL) were taken and evaporated to dryness under nitrogen at 60 ◦C. The residues were derivatised to form methyloximes by heating at 60 ◦Cfor1h with 50µL of methoxylamine hydrochloride (8%w/v in pyridine). Following derivatisation, 2 mL of cyclohexane: dodecane (98: 2 v/v) and 0.5 mL of water were added. The water layer was removed and anhydrous sodium sulphate was added to the organic layer, which was then decanted into a clean tube. The organic fraction was evaporated to dryness, the residue derivatised by trimethylsilylation and analysed by full-scan GC-MS, as described above. PublicNotices.Eu Michael R. Graham Analysis of Oral AAS PED tablets (Table 3) Nineteen products were analysed. Oral products (tablets) were placed into tubes containing 10 mL of methanol. The tubes were mixed thoroughly by sonication then centrifuged at 1320 g for 5 min. The equivalent of 1–5 µg of each substance was transferred to a glass tube, 0.1 mL of d3-testosterone solution (50 ng), 5 ml of potassium hydroxide (0.1 M) and 5 mL of hexane, were added. The contents were mixed thoroughly and then centrifuged at 1320 g for 5 min. The hexane layer was removed and added to 2 mL of 95% methanol, mixed thoroughly then centrifuged at 1320 g for 5 minutes. The hexane layer was removed and discarded. The methanolic layer was evaporated to dryness under a steady stream of nitrogen. The residues were derivatised to form ether-TMS and/or enol-TMS derivatives by heating at 60 ◦Cfor 15minwith40µL of a mixture containing N-methyl-Ntrimethylsilyltrifluoroacetamide (MSTFA), ammonium iodide and ethanethiol (1000/3/9 v/w/v). Following derivatization, the tubes were allowed to cool, 20 µL of dodecane was added and the samples were analysed by SIM and full-scan GC-MS as described above. Analysis of vials for human growth hormone and insulin-like growth factor-1 Long arm-3 Vials purported to contain h-GH and IgF-1 LR3 were subjected to direct analysis and following digestion with trypsin, using matrix-assisted laser desorption ionization time of flight, mass spectrometry (MALDI-TOF/MS) and peptide mass mapping, as described elsewhere [11]. The presence of recombinant h-GH (22.1 kDa) was investigated by peptide mass mapping (12 peptides). The presence of recombinant IgF-1 LR3 (7649 Da) was investigated by peptide mass mapping (70 amino acids). Results Table 1 identifies a new unlicensed counterfeit company (VMX Pharma) [12]. Retention times and full scan spectra were compared to those obtained from analysis of standards and drugs supplied by licensed pharmaceutical companies. The results of tablet, and vial analysis, obtained from the underground market, are displayed in Tables 2 and 3. Of the 22 samples analysed, 15 were counterfeit (68%). The statistical sign test applied to Tables 2 and 3 demonstrated significance in all groups (p < 0.05). From 12 vials for parenteral use, no samples contained what was described on the label (Table 2) and contained no active drug. Of the 10 oral preparations (Table 3), three products were counterfeit (30%). Seven products labelled contained the correct contents (70%). Microbiological culture of the vials revealed the presence of contaminants. Discussion Trade prices of black-market drugs appear to be decreasing, because of the enormous competition of illegal black market cottage industries and the pervasive invasion of the internet. In the UK, Europe and USA access to controlled drugs is uncontrolled and cannot be policed. However, in certain “communist” countries such as China certain websites, e.g., “Youtube” are banned (personal communications). Manufacturing costs in third world countries are fractional in comparison to UK costs, because of slave labour, using children in countries such as India, Thailand, Pakistan. Trade dealers will try and buy large quantities to obtain the cheapest prices and sell at retail for the maximum amount of profit (Table 1). One hundred percentage (100%) of the injectable PED AAS (Table 2) and thirty percentage (30%) of PED tablets (Table 3) were found to be counterfeit, containing steroids other than those indicated or no steroid at all. PublicNotices.Eu Michael R. Graham The risks of AAS abuse can be catastrophic to health [13] [14] [15]. Any unregulated manufacture may produce preparations that are contaminated with infectious agents and are of poor quality [16]. The sharing of AAS ‘multi-dose’ vials, whether the vials are from a legitimate source or otherwise, is common-place, exposing individuals to the risk of intramuscular abscesses. Reported infections associated with AAS injection include abscesses attributable to Mycobacterium smegmatis, Staphylococcus, Streptococcus, Pseudomonas, hepatitis B, hepatitis C and human immunodeficiency virus [17]. Administration of large volumes of testosterone esters in one injection (up to 5 mL) is common, exposing an individual to sterile abscess formation, where pathogenic organism cannot be found [18]. Contamination of vials with used needles would be an effective means of transmitting blood-borne pathogens [19] [20]] This is comparable to the sharing of spoons among intravenous drug users, who inject street drugs [21]. Education and provision of disposable of sterile needles remains a method to prevent such infections to this population [22]. However, there has been a pandemic increase in hepatitis C from recreational drug abuse and currently 50% of all recreational drug abusers are suffering with the virus [23]. There is a direct relationship between the increase in PED use and infections and communicable diseases, which are reaching plague magnitudes [24]. Funding for contemporary research must be provided to educate and prevent the catastrophic effects of doping [25]. However, the caveat to such measured bans on associated sporting personnel, must not rely on hearsay diatribe. Quasi-legal authorities cannot and must not falsify evidence to obtain a conviction at “any price”. Justice should be delivered in the fairest way possible examining hard factual evidence and not just hearsay opinion. Otherwise we may as well disqualify passengers from driving, when the driver is doing 100 m.p.h., in a 30 m.p.h., zone. It is considered gross professional misconduct not to treat drug addicts. A world famous professor once stated that we should give addicts not just what they want, but add harmful products to what they take (personal communications). Such opinion is atrocious. However, falsifying evidence to blame family members for crimes committed by their parents is equally heinous and considered “perverting the course of justice”. PublicNotices.Eu Michael R. Graham References 1. http://www.ukad.org.uk/news/article/first-ukad-lifetime-ban-following-policecollaboration.Accessed:01.08.2014. 2. R. J. Cramer, Anabolic steroids are easily purchased without a prescription and present significant challenges to law enforcement officials, http://www.gao.gov/new.items/d06243r.pdf, 3 November 2005.Accessed: 27.05.2014. 3. G. Hermansson, Doping trade: business for the big ones. Search for author under http://www.playthegame.org, January 2008.Accessed:21.6.2014. 4. M. R. Graham, B. Davies, F. Grace, A. Kicman, J. S. Baker, Sports Med. 2008, 38, 505. 5. Graham MR, Baker JS, Evans P, Hullin D, Thomas NE, Davies B.Potential benefits of recombinant human growth hormone (rhGH) to athletes. Growth Horm IGF Res. 2009 Aug;19(4):300-7. doi: 10.1016/j.ghir.2009.04.008. 6. http://www.timesonline.co.uk/tol/sport/more sport/athletics/artic le3942201.ece.Accessed:22.05.2014 7. http://news.bbc.co.uk/sport1/hi/olympics/athletics/7403158.stm,16 May 2008.Accessed:04.06.2014. 8. http://www.telegraph.co.uk/sport/othersports/boxing/9296051/Lamont-Petersonshould-get-a-life-ban-and-boxing-must-eradicate-drug-cheats-says-AmirKhan.html.Accessed:20.05.2014. 9. https://elb.wada-ama.org/en/what-we-do/investigationtrafficking/investigations.Accessed:07.05.2014. 10. E. Mikami, T. Ohno, H. Matsumoto, S. Sekita, J. Health Sci. 2003, 49, 547. 11. P.Laidler, D.A.Cowan, E.Houghton, A.T.Kicman, D.E.Marsh. Rapid Commun. Mass Spectrom. 1998, 12, 975. 12. http://www.pharmamedicexport.info.Accessed:13.05.2014. 13. M R Graham, F M Grace, W Boobier, D Hullin, A Kicman, D Cowan, B Davies, J S Baker. Homocysteine induced cardiovascular events: a consequence of long term anabolic-androgenic steroid (AAS) abuse. Br J Sports Med 2006;40:644–648. doi: 10.1136/bjsm.2005.025668. 14. Graham MR1, Ryan P, Baker JS, Davies B, Thomas NE, Cooper SM, Evans P, Easmon S, Walker CJ, Cowan D, Kicman AT.Counterfeiting in performance- and image-enhancing drugs. Drug Test Anal. 2009 Mar;1(3):135-42. doi: 10.1002/dta.30. PublicNotices.Eu Michael R. Graham 15. M. R. Graham, F. M. Grace, W. Boobier, D. Hullin, A. Kicman, D. Cowan, B. Davies, J. S. Baker, Brit. J. SportsMed. 2006, 40, 644. 16. M.Thevis, Y.Schrader, A.Thomas, G.Sigmund, H.Gey, W. Schanzer, J. Anal. Toxicol. 2008, 32, 232. 17. J. Rastad, H. Joborn, S. Ljunghall, G. Akerstrom, Lakartidningen 1985, 82, 3407. 18. M. D. Krauss, C. D. Van Meter, D. W. Robertson, Your Patient and Fitness 1995, 9, 12. 19. C. P. Marquis, N. Maffulli, Injury Extra 2006, 12, 451. 20. T. A. Buccilli Jr, H. R. Hall, J. D. Solmen, J. Foot Ankle Surg. 2005, 44,466. 21. M. J. Scott, M. J. Scott Jr., J. Amer. Med. Assoc. 1989, 262, 207. 22. P. M. Nemechek, New England J. Med. 1991, 325, 357. 23. P. Alcabes, G. Friedland, Clin. Infect. Dis. 1995, 20, 1467–79. 24. B. P. Dickinson, J. D. Rich, T. P. Flanigan, Anabolic steroid injectors and needle exchange programs in the United States: 1996. North American Syringe Exchange Network Conference, San Diego CA 1997, pp. 23. 25. C. Aceijas, T. Rhodes, Int. J. Drug Policy 2007, 18, 352. PublicNotices.Eu Michael R. Graham Table 1: Counterfeit Androgenic Anabolic Steroid (AAS): Manufacturing cost, Trade and Retail Prices Quantity Product (VMX) Administration Presentation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Tritren 200 Andro-Nex 250 Androplex 500 Equi-Lone 200 Masterone 100 IM IM IM IM IM IM IM IM IM IM IM IM Oral Oral Oral Oral Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Multidose (10 mls) Tablets Tablets Tablets Tablets Primobolan Depot 100 Nandrolone 200 Test Cypionate Test Enanthate Test Propionate Test 400 Trenbolone 80 Zanabol 10 Oxandrolone 50mg Oxydrol 50mg Stanozolol 50mg Key: Testosterone (Test); Manufacturing cost £ (Unknown) Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Unknown ? Trade Price £ (Variable) 23 17 21 18 18 20 16 15 15 13 19 19 25 28 28 28 Retail Price £ (Variable) 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 30-50 PublicNotices.Eu Michael R. Graham Table 2: Parenteral Products analysed by GC-MS and LC-MS/MS, which contained no active ingredients. Quantity Product label Product claimed 1 2 3 Boldabol Boldebal-h Mastabol 4 5 6 7 8 Primobolan Spectriol Testabol depot Testex elmu prolangatum 250 Tesosterone cypionate injection (cypionax) Trenbol 75-r Kigtropin Hygetropin Norditropin simplexx Boldenone undecylenate Boldenone undecylenate Dromastanolone dipropionate Methenolone enanthate T. Esters T. Cypionate T. Cypionate T. Cypionate 9 10 11 12 Key: Testosterone (T); Trenbolone acetate Growth hormone Somatotropin Growth hormone Product found Nil Nil Nil Nil Nil Nil Nil Nil Nil Nil Nil Nil PublicNotices.Eu Michael R. Graham Table 3: Oral products analysed by GC-MS and LC-MS/MS. Quantity 1 2 Product label Clenbuterol (Spiropent) Stanozolol 3 4 5 6 7 8 Stanozolol Methandienone Stanozolol Oxymetholone Ephedrine Stanozolol 9 10 Ma Huang Mesterolone (Proviron) Product found Clenbuterol No anabolic steroids detected 5α-dihydrotestosterone Methandienone Stanozolol Oxymetholone Ephedrine Methyl testosterone and caffeine Ephedrine Mesterolone
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