Medicine & Science in Sports & Exercise:
ACSM Position Stand: The Female Athlete Triad
ACSM Position Stand: The Use of Blood Doping as an Ergogenic Aid
Sawka, Michael N. Ph.D., FACSM, (Chair); Joyner, Michael J. M.D.; Miles, D. S. Ph.D., FACSM; Robertson, Robert J. Ph.D., FACSM; Spriet, Lawrence L. Ph.D., FACSM; Young, Andrew J. Ph.D., FACSM
Blood doping has been achieved by either infusing red blood cells or by administering the drug erythropoietin to artificially increase red blood cell mass. Blood doping can improve an athlete's ability to perform submaximal and maximal endurance exercise. In addition, blood doping can help reduce physiologic strain during exercise in the heat and perhaps at altitude. Conversely, blood doping is associated with risks that can be serious and impair athletic performance. These known risks are amplified by improper medical controls, as well as the interaction between dehydration with exercise and environmental stress. Finally, the medical risks associated with blood doping have been estimated from carefully controlled research studies, and the medically unsupervised use of blood doping will increase these risks. It is the position of the American College of Sports Medicine that any blood doping procedure used in an attempt to improve athletic performance is unethical, unfair, and exposes the athlete to unwarranted and potentially serious health risks.
This position stand addresses the practice of increasing red blood cell(RBC) mass-“blood doping”-for the purposes of improving exercise performance. RBC influence exercise performance because they carry oxygen to skeletal muscle and help maintain acid-base status. A modest (5%) increase in RBC mass is believed to be an adaptation to endurance training that takes several months to occur (41,53,73). However, some athletes have chosen to artificially increase their RBC mass by either infusing previously stored RBC or by taking the drug erythropoietin(EPO), which stimulates RBC production. Research has shown that artificially increasing RBC mass can improve a person's ability to perform endurance exercise and tolerate some environmental extremes(24,55,58).
It is the position of the American College of Sports Medicine that any blood doping procedure used in an attempt to improve athletic performance is unethical, unfair, and exposes the athlete to unwarranted and potentially serious health risks. It is acceptable, however, to artificially increase RBC mass for the purposes of medical treatment and legitimate scientific inquiry. Physicians increase RBC mass to improve the exercise capabilities of anemic patients suffering from kidney failure, AIDS, and other diseases. In addition, scientists increase RBC mass in research subjects (under controlled medical conditions) to enhance their understanding of physiologic responses to exercise and environmental extremes.
The lay press interest in blood doping stemmed from its alleged use in distance running, cycling, cross-country skiing, and biathlon events since the 1972 Olympics and during numerous world championships. Although many athletes have been accused of using blood doping, few have confessed. One notable exception were members of the United States men's cycling team at the 1984 Olympics, who confessed to infusing RBC before competition(16). Aside from any medals or illnesses believed to have resulted from blood doping, these athletes have lived with the stigma of cheating, which has overshadowed their athletic accomplishments.
Recently the lay press has speculated that EPO administration may have contributed to the deaths of eighteen European cyclists(22,71). This suspicion was because of: (a) the time-frame between appearance of commercial EPO and the cyclists deaths and(b) knowledge that some cyclists have previously used blood infusions to enhance performance. However, there is no evidence that these cyclists were under the influence of EPO, and the details on their deaths have not appeared in the medical literature.
Blood doping is considered an “ergogenic aid” within the context of sport and exercise performance. The sport practitioner considers an ergogenic aid to be a procedure or agent that provides the athlete with a competitive edge beyond that obtained via normal training methods(42). In contrast, the exercise scientist defines an ergogenic aid as an experimental procedure or agent that increases exercise performance in comparison to a placebo condition (42). An improvement in exercise performance is demonstrated in the laboratory by:(a) prolonging time to reach exhaustion at a given exercise intensity, (b) achieving a greater average power output for a given exercise duration, (c) achieving a greater maximal power output, and/or (d) achieving a shorter time to complete a given exercise task.
Ethical decisions regarding the use of blood doping as an ergogenic aid must consider the safety, legality, and effectiveness of the procedure. An ergogenic aid should be used in training and competition only when it has been unequivocally determined that the procedure has no attendant medical risks (i.e., safe), is within the rules governing a particular sport (i.e., legal), and produces the desirable improvement in competitive performance (i.e., effective). Blood doping does not meet the first two of these criteria with respect to competitive application.
The International Olympic Committee defines doping as the “use of physiological substances in abnormal amounts and with abnormal methods, with the exclusive aim of attaining an artificial and unfair increase of performance in competition” (18). Based on this definition, the International Olympic Committee has banned blood doping (RBC infusion and erythropoietin administration) as an ergogenic aid.
RBC mass can be artificially increased either by infusing RBC or by administering EPO. Infusing RBC produced by oneself (autologous infusion) or another person (homologous infusion) will rapidly increase RBC mass but this increase will be sustained for only several weeks (37). Administering EPO will slowly increase the number of RBC over several weeks but the increase will be sustained as long as EPO treatment continues.
For autologous infusion, several blood units (≈450 ml each) are removed by phlebotomy, the RBC are harvested, stored, and later reinfused. Each phlebotomy is spaced by several weeks so that normal hematocrit can be reestablished prior to the next phlebotomy or reinfusion. For autologous infusions, glycerol freezing techniques are needed to allow prolonged RBC storage without degradation (65). For homologous infusions, refrigeration techniques may be used for short-term storage; however, RBC will progressively degrade and the maximum storage period is about 42 d. Blood storage and handling techniques are important as they influence RBC function and survival rate which contributes to interstudy dose-response variability.
EPO is primarily produced in kidneys and stimulates RBC production in bone marrow (34). Recently, the EPO gene was cloned and genetically engineered so that EPO became commercially available(21,30). Clinically, EPO is primarily given to kidney failure patients in conjunction with their hemodialysis, but this drug is also given to trauma, AIDS, and other anemic patients(1,26,57). Patients who received intravenous (I.V.) dosages of EPO demonstrated fairly uniform dose-dependent increases in hemoglobin over many weeks (49), and clinical studies indicate that subcutaneous (S.c.) administration allows blood EPO levels to be maintained using less frequent administration at lower EPO dosages than I.V. administration (33,49).
The effectiveness of RBC infusion and EPO administration on increasing the number of RBC is best quantified by measuring RBC mass via radioactive isotope technologies (53); however, many hospitals and research laboratories do not have these capabilities. Therefore, simple clinical indices, such as hematocrit or hemoglobin concentration, are often used to estimate changes in RBC mass. These clinical indices are influenced by independent effects of both RBC mass and plasma volume; so if either RBC infusion or EPO administration would also alter plasma volume, then these indices would provide inaccurate estimates of RBC mass changes.
Several studies have performed blood volume measurements on persons both before and after either RBC infusion(29,50,52,54) or EPO administration(19,31,36). Generally, those studies report that adding “extra” RBC causes a compensatory reduction in plasma volume to maintain the same initial blood volume(31,36,50,54); however, this is not always the case (52). Therefore, the use of only hematocrit and/or hemoglobin values to quantitate the amount of“extra” RBC will usually result in an overestimation of the RBC mass increase after either RBC infusion or EPO administration. These clinical indices (hematocrit and hemoglobin), however, do accurately estimate the increased oxygen carrying capacity and viscosity changes associated with“extra” RBC.
Differences in RBC survival and plasma volume responses to infusion make it difficult to compare dose (amount of RBC infused)-response(increase in hematocrit or hemoglobin) characteristics between studies. For a given person, the more RBC infused the greater the increase in hemoglobin. For example, Spriet et al. (59) reported that when healthy subjects were infused the RBC product of two blood units, hemoglobin increased by ≈8% and when infusing the RBC product of three blood units, hemoglobin increased by ≈10%. When comparing healthy subjects, the magnitude of the hemoglobin increase is quite variable for a given amount of RBC infused. For a group of 21 healthy subjects, infusing the RBC product of two blood units increased hemoglobin ([horizontal bar over]X ± SD = 10% ± 5%) by a range of 2%-18% (56).
Limited data are published regarding EPO dose-response characteristics for healthy subjects. Berglund and Ekblom (4) compared two S.c. dosages of EPO for increasing hemoglobin in healthy subjects. Eight persons were given S.c. 20 U·kg-1 EPO three times per week for 6 wk and another seven persons were given S.c. 20 U·kg-1 EPO three times a week for 4 wk, followed by 40 U·kg-1 EPO for the next 3 wk. For both groups, hemoglobin increased (0.28 g·wk-1) in a linear manner and was 11% greater after 6 wk. Casoni and colleagues(13) administered S.c. 30 U·kg-1 EPO every other day for 6 wk to 20 healthy subjects and found that their hemoglobin increased by 6%.
Maximal Aerobic Power
A high maximal aerobic power (or maximal oxygen uptake, ˙VO2max) is important to succeed in athletic events requiring sustained activity at high metabolic rates; therefore, ˙VO2max increases often translate into improved athletic performance. ˙VO2max is defined as the maximal rate at which oxygen is being utilized by body tissues during physical exercise and is dependent upon both central circulatory (oxygen delivery) and peripheral (oxygen extraction) factors. Oxygen delivery to working muscles is a function of muscle blood flow and oxygen content of blood. If blood doping increases hemoglobin concentration then oxygen content will increase, as each gram of hemoglobin carries about 1.34 ml of oxygen, and oxygen delivery will be increased providing that blood flow is not correspondingly decreased.
Investigators who infused the RBC product of 2 blood units reported˙VO2max increases of 4%-11%(9,11,14,43,50,52,59,62,64). Investigators who infused the RBC product of 3-5 blood units reported that infusion of the second through fifth units produced additional increases in˙VO2max (14,59). Numerous studies have demonstrated that EPO administration will markedly increase ˙VO2max of anemic hemodialysis patients(3,27,32,36,47). RBC infusion and EPO administration, however, seem to provide similar ergogenic effects for a given increase of hemoglobin in healthy persons(19).
Investigators (32,36,46,56) report that the relationship between changes in hemoglobin/hematocrit and changes in ˙VO2max after blood doping are strong with group analyses, but do not hold well with individual subject analyses. Therefore, it appears that a person's ergogenic response to blood doping might depend on a variety of physiologic factors such as genetics, fitness level, and training state (56).
When ˙VO2max is increased following blood doping, a given absolute power output represents a lower percentage of the new˙VO2max (lower relative power output). For example, in one study the power output representing 91% of the predoping ˙VO2max was only 87% and 85% of the new ˙VO2max values following the reinfusion of RBC from 2 and 3 blood units, respectively (59). Consequently, many investigations report unchanged ˙VO2, lower heart rates, lower venous and arterial lactate, and higher venous and arterial pH values at a standardized submaximal power output following blood doping(11,14,19,20,43,45,59). This reduced physiologic strain should contribute to improved submaximal performance after blood doping.
Numerous laboratory tests have been used to assess blood doping effects on submaximal performance. For highly trained male runners, RBC infusion improved run time to exhaustion at 95% of the preinfusion ˙VO2max by 20% and 34% (control run, ≈7 min) at 24 h and 7 d, respectively(11). Another group of well trained male distance runners improved their 5-mile treadmill run times by ≈2% after RBC infusion, with most of the reductions occurring in the final 2 miles(69). Trained male mountain climbers demonstrated a 16% increase in treadmill run time during a multistage test after RBC infusion(45). Untrained men ran on a treadmill 13% longer at the same%˙VO2max (≈67% pre- and post-) after RBC infusion(63). For active women, time to exhaustion increased by 19%-26% during a progressive cycle ergometer test after RBC infusion(43).
EPO administration improved run time to exhaustion by 17% during a progressive treadmill test in recreationally trained men(19). Likewise, investigations have shown that EPO administration to anemic adults and children with renal disease increases their physical work capacity by ≈10%-100%(3,7,12,15,27,34,36,47).
Studies examining the effectiveness of blood doping on race performance have consistently reported improvements, primarily in the distance as opposed to shorter events. For trained distance runners, RBC infusion decreased 3-mile run time by ≈24 s, and a sham reinfusion had no effect(25). For cross-country skiers (single-blind design), 15-km race times decreased by 5% and 3% at 3 h and 14 d post-infusion, respectively (5). For male distance runners (double-blind design), 10-km run times decreased by 69 s after RBC infusion(8). In another study (double-blind design), the same investigators found that RBC infusion decreased 1500-m run time on a track by≈5 s (9). In both studies sham infusions had no effect on race time.
Recently, an analysis of cumulative improvement in run time after RBC reinfusion (product of 2 blood units) as a function of race distance was performed (58). The data used in the analysis were derived from the one laboratory and three field studies cited above where male subjects participated in running races over distances of 1500 m to 10 km. The cumulative post-reinfusion improvement in run time increased as a function of the completed distance, such that predicted run times improved ≈7, ≈30, and ≈68 s at distances of 2, 6, and 10 km, respectively.
When ascending to high altitude, reduced oxygen pressure in inspired air decreases arterial oxygen tensions; thus, oxygen saturation of hemoglobin falls, and in turn, the arterial oxygen content declines. There is little measurable ˙VO2max decrement below 1000 m, a small variable decrement between 1000 and 2000 m, and above 2000 m a linear decrement by 10% for every additional 1000 m ascended. Endurance, or time to exhaustion during prolonged submaximal exercise, is similarly diminished at high altitude.
Few studies have investigated the effects of blood doping on persons exposed to high altitude. In 1947, Pace et al. (38) demonstrated that subjects infused with 1000 ml of RBC exhibited lower heart rates while walking at a simulated (hypobaric chamber) altitude of 4712 m compared with control subjects. Heart rates of RBC-infused subjects at this altitude were comparable to those of control subjects exercising 1581 m lower. This observation gave rise to the concept that blood doping conferred an“altitude-lowering” effect.
Later, Robertson et al. (45) reported that exposure to a simulated (hypoxic gas breathing) altitude of 3566 m reduced˙VO2max only 10% in subjects who had been infused with 750 ml of RBC, compared with a 20% ˙VO2max reduction observed in the same subjects before RBC infusion. Subsequently, the same investigators(44) reported that at a lower simulated altitude of 2255 m, infusion of 334 ml of RBC completely prevented the 10% decrease in˙VO2max observed during hypoxic exposure before infusion.
The blood doping studies by Pace et al. (38) and Robertson et al. (44,45) used simulated altitude conditions consisting of fairly brief (less than 1 h) periods in a hypobaric chamber or breathing hypoxic gas mixtures. Young and colleagues(72) studied the effects of blood doping on sea level residents who rapidly ascended to the summit of Pikes Peak, 4300 m, and remained for 15 d. Subjects infused with 290 ml of RBC the day before ascending experienced a 25% decline in ˙VO2max, which was not significantly different from the 28% decline experienced by control subjects(72). Further, 2-mile (outside course) run time at 4300 m did not significantly differ between blood-doped and control subjects, although the blood-doped subjects tended to show more improvement in run time following 9 d of altitude acclimatization (39).
Several interpretations emerge from the different studies reviewed. The ergogenic effects of blood doping may diminish as altitude increases. Thus, at sea level, blood doping increases ˙VO2max, and at relatively low(<2500 m) altitudes, blood doping may prevent hypoxic-related decrements in˙VO2max (44). In persons ascending to moderate (>2500 but < 3800 m) altitudes, blood doping may lessen but not completely prevent the decline in ˙VO2max(45), whereas effects of blood doping on˙VO2max may be negligible at higher altitudes(72). Another possibility is that ergogenic effects are apparent only with acute hypoxic exposure, and that acclimatization occurring with exposures lasting more than a few hours somehow obviates ergogenic effects. A final consideration is that the induced hemoglobin increase was smaller in the 4300 m experiments (72) than in the studies at lower altitudes where ergogenic effects(44,45) were demonstrated.
Several mechanisms might enable blood doping to provide an ergogenic benefit for persons exercising in the heat. The magnitude of core temperature increases during exercise is related to relative exercise intensity(%˙VO2max) (55). Therefore, smaller core temperature increases could occur during exercise following blood doping. Additionally, the increased arterial oxygen content, induced by blood doping, might allow systemic oxygen transport requirements for a given level of submaximal exercise to be achieved with lower muscle blood flow. This should alleviate some competition between circulatory requirements of metabolism and heat dissipation and enable redistribution of blood flow to skin. Furthermore, if blood doping increased blood volume, that might serve as a reserve to support thermoregulation.
Two investigations have studied the potential ergogenic effects of blood doping for persons exercising in the heat. Sawka and colleagues(50) had unacclimated men walk in the heat both before and 48 h after being infused with 300 ml of RBC. Blood doping reduced heat storage and increased sweating sensitivity but did not alter core temperature during exercise (50,51). In addition, blunted heart rate (50) and cortisol (23) responses were observed. The significance of the small thermoregulatory advantage and reduced physiologic strain after blood doping appeared questionable in light of the pronounced benefits conferred by heat acclimatization.
Subsequently those investigators (52) examined whether blood doping would provide any thermoregulatory advantage to heat acclimated persons exercising in the heat and whether dehydration would obviate any benefit (or perhaps illuminate an unrecognized disadvantage) resulting from blood doping. Before and after (2-4 d) being infused with≈300 ml of RBC, heat acclimated men walked in the heat, once while normally hydrated and, on a separate day, while dehydrated by 5% of their body weight. Blood doping provided a substantial thermoregulatory advantage regardless of hydration status. This was demonstrated by lowered core temperatures, sweating thresholds, and heart rates and increased sweating sensitivity during exercise following blood doping both when euhydrated and hypohydrated(51,52).
Thus, blood doping can be an ergogenic aid for people exercising in the heat. Blood doping confers a thermoregulatory advantage which appears greatest for heat acclimated persons and is only slight for unacclimated people.
Ergogenic effects of blood doping have not been evaluated under cold stress conditions. There is no reason to believe that the improved ˙VO2max observed in temperate environments after blood doping would be any less apparent with cold stress. Thus, blood doping might enable shivering and/or voluntary physical activity to be sustained longer or more vigorously. On the other hand, blood doping might increase susceptibility to peripheral cold injury (e.g. frostbite, trenchfoot) if blood viscosity increased sufficiently to impair microcirculation during cold-induced vasoconstriction. In the absence of experimental data, these effects remain only speculative.
High Hematocrit Risks
Viscosity increases vascular resistance independently of blood vessel diameter and requires more forceful cardiac contractions to circulate the blood (28,60). Blood viscosity rises exponentially as hematocrit increases above 30% (35). At very high hematocrits (i.e., clinical polycythemia, hematocrit ≥ 55%) the physiologic disadvantages of hyperviscosity might be detrimental to exercise performance and health. For athletes who compete or train while blood doped, such high hematocrits can be achieved through a combination of the“extra” RBC and dehydration, which lowers plasma volume.
The sluggish blood flow associated with very high hematocrit is believed(as these risks are not documented for healthy persons) to increase the risks of thromboembolic events such as stroke or myocardial infarction. It can also cause venous stasis in small vessels and perhaps thrombosis, which may contribute to deep venous thrombosis and pulmonary embolism. Patients with pathologic conditions (such as Polycythemia Vera) who have hematocrits of ≥ 55% will undergo thorough medical evaluation and often be phlebotomized to lower their hematocrit. Recently, it was reported that blood doping did not increase fibrinolytic activity in healthy subjects exposed to high altitude, despite having hematocrits of 52% and 55% at rest and after maximal exercise, respectively (40).
The risk associated with receiving one unit of appropriately screened and tested RBC from a homologous transfusion is estimated to be about 1 in 200,000 for hepatitis B, and between 1 and 3 in 10,000 for hepatitis C(17). However, the risk for a serious irreversible liver disease or death from hepatitis C is probably much lower; 1 in 10,000-20,000. The risk for HIV (AIDS) infection ranges from 1 in 150,000 in the southeastern United States, to 1 in 1,000,000 in the central United States(2). The overall risk for the entire United States for HIV infection is 1 in 340,000 (2). Other risks from banked blood include major transfusion reactions from blood type incompatibility on the basis of clerical error, minor transfusion reactions including fever and body aches, transfusion-related acute lung injury, and bacterial infection (48). The overall risk that a blood recipient will contact a serious or fatal transfusion transmitted disease is about 3 in 10,000 (17,66).
Press reports indicate that athletes have received improperly screened and tested homologous blood transfusions from friends and family members(16). The risk of medically unsupervised transfusion is certainly greater than that associated with receiving appropriately screened blood products on the basis of medical need. Additionally, it can be argued that the risk of receiving blood products from family members or friends is actually higher than that associated with receiving blood from an anonymous volunteer donor since friends and family members may be less likely to reveal potential behavioral risk factors for infectious disease transmission.
Autologous infusion of RBC is not perfectly safe. Clerical error, mislabeling, and mishandling of blood products are the most common causes of serious infusion-related morbidity. Although this is infrequent, the risk of clerical error is the same for autologous as homologous blood transfusion(17,66). Also, persons receiving autologous infusions have the risk of bacterial infections on the basis of mishandled blood products (17,66).
EPO causes few side-effects and those reported are not necessarily attributed to the drug (58,70). For hemodialysis patients, EPO has been associated with an increase in arterial blood pressure(12,61). The European Multicenter Study reported that EPO (median weekly dose of ≈250 U·kg-1, I.V.) increased mean arterial pressure (at rest) from 95 to 99 mm Hg at 6 months, but was not increased (97 mm Hg) after 1 yr (61). The Canadian Multicenter Study reported EPO (≈300 U·kg-1, I.V.) did not alter systolic blood pressure (at rest), but diastolic blood pressure increased from 78 to 85 mm Hg after 6 months (12). The incidence of blood pressure elevation seems to be related to the EPO dosage(10).
There is some evidence that the blood pressure of healthy adults might be affected by EPO. Berglund and Ekblom (4) studied blood pressure responses in healthy physical education students receiving EPO(≈30 U·kg-1, S.c.) for 6-7 wk. They reported no difference in systolic or diastolic blood pressure at rest or systolic blood pressure during light intensity (100 W) exercise. During moderate intensity exercise (200 W) systolic blood pressure increased from 177 to 191 mm Hg after EPO. Therefore, increased blood pressure should be considered as a potential risk factor for EPO in athletes.
Other side effects associated with EPO have included flu-like symptoms and hyperkalemia. Flu-like symptoms are usually mild and do not persist(70). Increased plasma potassium levels have been reported in dialysis patients receiving EPO therapy; the rise seems to be greatest during the beginning of treatment (70). Healthy persons receiving multiple injections of EPO may have an inhibition of their endogenous EPO production (68). This inhibition probably does not occur until EPO administration has increased RBC mass above normal levels from the treatment (68).
The testing of athletes for ergogenic aids is presently restricted to urine samples. The use of blood samples would improve the ability to detect blood doping.
Homologous transfusion. It is possible to test for subtle antigenic differences in blood samples to determine whether an athlete has received RBC from another person. However, since the use of homologous blood to improve athletic performance is thought to be rare, the effort involved may not be worth the benefit to fair competition(6,13).
Autologous infusion. It is difficult to test for autologous blood transfusions. While there are some subtle changes in RBC shape as the cells“age” while stored, it is difficult to develop a highly reliable test on the basis of these changes (6,13).
EPO. EPO can cause changes in RBC size, RBC hemoglobin content, and other parameters that may be detectable on routine hematologic screening. However, these indices might also change as a result of exercise and environmental exposure and may lack the reliability required to conclusively test for EPO use (6). Additionally, since EPO is a peptide hormone, the half-life of exogenously administered EPO will be short while the physiologic effects will be long (49). This makes it difficult to develop highly reliable tests using EPO concentration levels to detect its use (49,68).
DNA-recombinant human EPO is less negatively charged and has less electrophoresis mobility than endogenous EPO in healthy persons(67). Wide and colleagues (68) have successfully used this information to detect the presence of exogenously administered EPO. They reported that when exogenous EPO was administered it could be detected in serum samples for up to 3 d after injection and in urine samples for up to 2 d after injection with no false-positive results(68).
It is the position of the American College of Sports Medicine that any blood doping procedure used in an attempt to improve athletic performance is unethical, unfair, and exposes the athlete to unwarranted and potentially serious health risks. Blood doping can improve an athlete's ability to perform submaximal and maximal endurance exercise. In addition, blood doping can help reduce physiologic strain during exercise in the heat and perhaps at altitude. All blood doping procedures have attendant medical risks that can be serious and reduce athletic performance. These known risks are amplified by improper medical controls, as well as the interaction between dehydration with exercise and environmental stress. Finally, the medical risks associated with blood doping have been estimated from carefully controlled research studies and medically unsupervised use of blood doping will increase these risks.
This position stand replaces the 1987 ACSM position paper, “Blood Doping as an Ergogenic Aid.”
This pronouncement was reviewed for the American College of Sports Medicine by members-at-large, the Pronouncements Committee, and by: E. R. Eichner, M.D., FACSM, R. Gotshall, Ph.D., C. Robert Valeri, M.D., and Melvin H. Williams, Ph.D., FACSM.
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