To help clinicians understand the risks associated with performance-enhancing drugs, this overview covers prohibited lists of substances and methods, therapeutic use exemptions, the legitimate indications and adverse effects, including for megadose and polypharmacy doping of stimulants, anabolic steroids, erythropoiesis-stimulating agents, and growth hormone and ways in which physicians or patients risk committing anti-doping rule violations inadvertently.
Key points
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The risks associated with taking performance-enhancing drugs concern users other than athletes because the general public, including youth, also takes them.
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The risks go beyond textbook side effects because adverse reactions can be triggered by megadoses, polypharmacy practices, drugs unapproved for human use, and exercise.
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Athletes who need a prohibited substance for legitimate medical reasons can request a Therapeutic Use Exemption with their physician’s help.
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A positive anti-doping test is only 1 of 10 ways to commit an anti-doping rule violation.
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Athletes are not the only ones at risk for violating anti-doping rules. Physicians and other entourage members can do so even inadvertently.
Introduction
Risk in sport takes many shapes, and doping issues add many ways for athletes and their health care professionals to violate the rules. In addition to the adverse effects of misused pharmaceuticals, dopers are at risk for toxicity with black market products unapproved for human use, and clean athletes are at risk for inadvertent doping offenses because of dietary supplement contamination or failure to respect administrative procedures, to give only a few examples. Some unethical physicians deliberately engage in doping activities, as highlighted by occasional sports headlines. However, in this article the case examples were selected to illustrate how even honest physicians and athletes have also had to cope with doping problems.
Introduction
Risk in sport takes many shapes, and doping issues add many ways for athletes and their health care professionals to violate the rules. In addition to the adverse effects of misused pharmaceuticals, dopers are at risk for toxicity with black market products unapproved for human use, and clean athletes are at risk for inadvertent doping offenses because of dietary supplement contamination or failure to respect administrative procedures, to give only a few examples. Some unethical physicians deliberately engage in doping activities, as highlighted by occasional sports headlines. However, in this article the case examples were selected to illustrate how even honest physicians and athletes have also had to cope with doping problems.
Overview
Anti-Doping Programs
Doping is prohibited in most sports. Anti-doping programs should include the following:
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A written drug-testing protocol
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A list of prohibited substances and methods
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A consent form
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A process for athletes to request permission to use a banned substance for legitimate medical treatment (Therapeutic Use Exemption [TUE])
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Sanctions
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An appeal process
Athletes in Olympic sports are subject to the rules of their sports federations, which are signatories to the World Anti-Doping Code. The National Collegiate Athletic Association (NCAA) and professional sports organizations, such as Major League Baseball (MLB) or the National Football League (NFL), also conduct anti-doping programs.
Prohibited Lists
For a given athlete, the relevant prohibited list depends on which sport authority has jurisdiction over the athlete, which may depend on the event. For example, it would be the NCAA Banned Drugs list when competing at the NCAA Championships, but the World Anti-Doping Agency (WADA) Prohibited List at the Olympics.
WADA’s harmonization efforts have led sports and national anti-doping organizations (eg, the United States Anti-Doping Agency [USADA]) to accept and implement the Code, including by adopting the WADA Prohibited List. To reflect trends in drug use, WADA updates the list annually as one of its responsibilities for monitoring anti-doping worldwide.
Substances or methods are considered for inclusion on the list if they meet any 2 of the following 3 criteria:
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Scientific evidence of (potential) sport performance enhancement
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Scientific evidence of (potential) health risk
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Violation of the spirit of sport
Alternatively, a single criterion is that the substance or method could mask doping.
One skeleton athlete paid a high price for missing an update. He was using finasteride to treat alopecia and did not notice when WADA banned the drug as a masking agent in 2005. After a positive test and appeal procedures, he was barred from the 2006 Turin Olympics. By 2009, testing advances made it possible to remove finasteride from the banned list.
To help athletes and their entourage stay up to date, WADA makes its list available as an App, USADA helps to manage a global drug reference online database ( www.globaldro.org ), and the National Center for Drug Free Sport, which manages the NCAA drug testing program, operates the Resource Exchange Center, a drug information service to which anti-doping programs (eg, NCAA, MLB) can subscribe so that their athletes can consult it.
The WADA list ( Table 1 ) includes 14 classes of substances and methods. The substances are banned with no threshold (ie, at any urinary concentration), with few exceptions. To cover drugs not named as examples, several classes (eg, steroids, stimulants), include “other substances with a similar chemical structure or similar biological effect(s).”
| Prohibited Substances | Examples |
|---|---|
| Substances and methods prohibited at all times (in competition and out of competition) | |
| S0. Nonapproved substances a | Rycals (eg, S107, a Ca 2+ channel stabilizer that improves impaired contractility, such as in heart and skeletal muscle), LH receptor agonists |
| S1. Anabolic agents | |
| 1. Anabolic androgenic steroids | |
| a. Exogenous | Stanozolol, nandrolone, methandienone, boldenone, dehydrochloromethyltestosterone b , c |
| b. Endogenous | Testosterone, dehydroepiandrosterone b |
| 2. Other anabolic agents | Clenbuterol, tibolone, selective androgen receptor modulators (SARMs) |
| S2. Peptide hormones, growth factors, and related substances | |
| 1. Erythropoiesis-stimulating agents | Erythropoietin (EPO), darbepoetin b |
| 2. Chorionic gonadotropin (CG) and luteinizing hormone (LH) in males | CG, LH b |
| 3. Corticotropins | Tetracosactide hexaacetate (Synacthen) |
| 4. Growth hormone (GH) Insulin-like growth factor 1 (IGF-1) Fibroblast growth factors (FGFs) Hepatocyte growth factor (HGF) Mechano growth factors (MGFs) Platelet-derived growth factor (PDGF) Vascular-endothelial growth factor (VEGF) | |
| S3. β2-Agonists | Terbutaline, salbutamol, fenoterol, salmeterol b |
| S4. Hormone and metabolic modulators | |
| 1. Aromatase inhibitors | Letrozole, androstatrienedione, anastrozole, formestane, androstene-3,6,17-trione (6-oxo) |
| 2. Selective estrogen receptor modulators | Tamoxifen |
| 3. Other antiestrogenic substances | Clomiphene |
| 4. Agents modifying myostatin function(s) | Myostatin inhibitors |
| 5. Metabolic modulators a. Insulins b. Peroxisome proliferator activated receptor δ (PPARδ) agonists (eg, GW 1516), PPARδ-AMP-activated protein kinase (AMPK) axis agonists (eg, AICAR) | PPARδ agonists |
| S5. Diuretics and other masking agents | Furosemide, hydrochlorothiazide, chlorothiazide, canrenone, acetazolamide, indapamide b–d |
| Substances and methods prohibited in competition | |
| S6. Stimulants | Methylhexaneamine (dimethylpentylamine), cocaine, amphetamine, methylphenidate, methamphetamine ( d -) b , c for some stimulants |
| S7. Narcotics | Morphine, oxycodone, fentanyl and derivatives, methadone b |
| S8. Cannabinoids | Carboxy-THC, JWH-018, JWH-073 b |
| S9. Glucocorticosteroids | Budesonide, prednisolone, prednisone, betamethasone, dexamethasone b |
| M1. Manipulation of blood and blood components |
|
| M2. Chemical and physical manipulation | Tampering by urine substitution or adulteration (eg, proteases) |
| M3. Gene doping | Using polymers of nucleic acids or genetically modified cells |
| Substances prohibited in particular sports | |
| P1. Alcohol | |
| P2. β-Blockers | Metoprolol, atenolol, labetalol, acebutolol, bisoprolol, propranolol, sotalol b |
a Any pharmacologic substance not addressed by any of the other sections of the List and with no current approval for human use by any governmental regulatory health authority.
b Examples listed in order of decreasing frequency of identification by laboratories in 2012.
c And other substances with a similar chemical structure or similar biological effect(s).
The 2013-2014 NCAA Banned Drugs list also includes any chemically related substance. As an example of a difference between different organizations’ lists, caffeine is banned by the NCAA (if >15 μg/mL urine), but not by WADA, although it is included in WADA’s 2014 Monitoring Program to detect abuse patterns. There is thus a risk for athletes being misinformed about which list applies in competition or at all times, and testing positive.
Therapeutic Use Exemptions
For athletes who need a prohibited drug for legitimate medical reasons, comprehensive anti-doping programs offer a way to request a TUE. WADA rules may allow athletes to possess or use a prohibited substance or method without violating anti-doping rules if the conditions in Box 1 are satisfied.
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The prohibited substance or method is needed to treat a medical condition and withholding such treatment would result in a significant impairment to the athlete’s health
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The therapeutic use of the substance or method is highly unlikely to enhance performance beyond returning the athlete to a normal state of health
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That there is no reasonable, permitted alternative must be clinically justified
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The need to use the substance or method is not a consequence of prior doping
Such athletes must provide a statement by an appropriate physician, attesting to the need to use the prohibited substance or method, to treat a documented medical condition. TUE applications must specify dosage, frequency, route, and duration of administration.
TUEs must be obtained before possessing the substance, using it, and potentially testing positive for it at a time when it is banned, whether in competition or during training, so it is best to allow ample time by applying as soon as the need is known. A common reason for delays is that incomplete or illegible applications are returned for resubmission. The TUE committee reviewing the application may need extra time to request additional information or consult other experts. Any change in dosage, frequency, route, or dates of administration requires obtaining a new TUE first. Retroactive TUE approval is possible after emergency treatment or in exceptional circumstances where there has been insufficient time to obtain a TUE first (eg, short-term use of narcotic analgesics).
If possession of a substance or its presence in urine or blood is not consistent with the terms of a TUE, the athlete may be charged with an anti-doping rule violation. Athletes risk committing such violations owing to the inadvertent lack of a TUE, because it was not requested, was requested too late, was requested for the wrong drug, dose, frequency, or duration (start and end date), or was not renewed in time.
What Happens to a Positive Test?
Following a laboratory report of an “adverse analytical finding” (eg, the presence of a prohibited substance in an athlete’s sample), the anti-doping organization may impose individual or team sanctions. Appeals are typically subject to arbitration (eg, before the Court of Arbitration for Sport [CAS] in cases involving WADA signatories).
If a prohibited drug is present, a sanction is imposed, regardless of how the drug got there and whether the athlete was aware of it. Strict liability has consistently been upheld by CAS beginning even before the unfortunate case of a gymnast at the 2000 Sydney Olympics. She tested positive for pseudoephedrine, which her team physician had given her for a cold. She lost her gold medal and her appeal to CAS. Her physician was expelled from the Games and barred from the next 2 Olympics. In 2004 WADA removed pseudoephedrine from the prohibited list, but global monitoring showed increasing urinary concentrations as evidence of abuse, so in 2010 WADA banned pseudoephedrine again.
Selected drug classes
The most problematic classes of substances prohibited by WADA are covered here. Stimulants, anabolic androgenic steroids, and drugs that enhance oxygen transfer are substantially misused for doping because they enhance performance. Growth hormone is a hotly debated issue. The WADA 2012 statistics list the substances identified in 267,645 samples from more than 90 sports tested by the 34 WADA-accredited laboratories worldwide. The substances most often reported within each class are discussed.
Stimulants
Legitimate medical indications
Among the 5 prohibited stimulants most often identified in athletes’ urine samples by WADA-accredited laboratories worldwide are amphetamine, d -methamphetamine, and methylphenidate. Amphetamine and combinations of its derivatives are indicated for the treatment of attention-deficit/hyperactivity disorder (ADHD) and narcolepsy. Methamphetamine is approved for use in weight-loss treatments for simple obesity and for the treatment of ADHD. Methylphenidate indications include the treatment of ADHD, autistic disorder, bipolar disorder, and narcolepsy.
Misuse
Stimulants have enjoyed popularity in a variety of sports owing to their purported ability to increase energy and concentration, and because they enhance performance. In the NFL, the “Sunday syndrome” referred to amphetamine highs and lows. In Major League Baseball, “greenies” were the green clobenzorex capsules used in the 1980s and 1990s.
The latest NCAA study of substance abuse by athletes revealed that 5% of athletes across all sports had used amphetamines, ephedrine, or both in the preceding year. Interestingly most of the amphetamine users stated that athletic performance was not their main reason for use. Perhaps it was to improve studying, which may explain why 6% had taken Adderall or Ritalin without a prescription. Almost 8% of male wrestlers had used amphetamines, and clinicians should be aware that athletes use stimulants to lose weight in sports with weight classes.
Adverse effects
The side effects of stimulants are associated with central nervous system and cardiovascular stimulation. With amphetamine-like compounds, beyond tremor, tachycardia, insomnia, and other well-known adverse effects, severe effects include myocardial infarction, stroke, and death. Adverse effects of methylphenidate also include Raynaud phenomenon, diaphoresis, and decreased appetite.
The demands of sports can increase the thermogenic effects of stimulants and cause heat illness, perhaps because of increased muscle mass in athletes or because stimulants can reduce skin blood flow and limit cooling. Indeed, ephedrine was a contributing factor in several heat-related deaths of American football players. Exercise can also trigger cardiac arrhythmias, and stimulants, which are arrhythmogenic, heighten such risk. It is imperative for sports medicine professionals to be aware of these complications when assessing athletes, and to know which athletes have TUEs for stimulants.
The stimulant most often reported in athletes’ samples by WADA laboratories in 2012 was methylhexaneamine (1,3-dimethylamylamine [DMAA]) in 320 samples. Although DMAA was once marketed as a nasal decongestant, it no longer has any Food and Drug Administration (FDA)-approved medical indication in the United States. Nonetheless, it is sold as a dietary supplement promising weight loss, muscle building, and performance enhancement. In 2012, the FDA began warning supplement manufacturers that products containing DMAA are illegal. By 2013, the FDA had received 86 reports of illnesses and deaths associated with DMAA-containing supplements. The illnesses consisted of cardiac complications and nervous system or psychiatric disorders. One study noted significant blood pressure increases following DMAA consumption. There is also a case report of a young man suffering a cerebral hemorrhage after ingesting DMAA with caffeine and alcohol.
Anabolic Androgenic Steroids
Legitimate indications
The primary therapeutic use of anabolic androgenic steroids (AAS) is to treat testosterone (T) deficiency. T is indicated for the treatment of hypogonadism in males and delayed puberty in adolescent males, and also used to treat symptoms of T deficiency.
Stanozolol, the exogenous AAS most often reported by WADA laboratories in 2012, is approved in the United States for the treatment of hereditary angioedema. It is less androgenic than T. Veterinary stanozolol has been used to treat debilitated horses and to help horses recover from surgery or injuries.
Nandrolone was approved by the FDA for the treatment of anemia in chronic renal failure, and has been used as an off-label treatment for inoperable metastatic breast cancer in women, but it has not been legally available in the United States since 2007. It is less androgenic than T.
Misuse
AAS studies in the 1960s, using replacement or therapeutic doses, found no evidence of an anabolic effect. Not until 1996 did Bhasin and colleagues demonstrate that supraphysiologic doses are required for muscle building. However, athletes knew this well before 1996, as did the government officials running the former German Democratic Republic’s systematic sports doping program. Users combine multiple AAS (“stacking”), increase then decrease doses (“pyramiding”) during each cycle of use, and cycle on and off to let their hormonal systems recover ; take human growth hormone (hGH) ; and add drugs to counteract AAS side effects (eg, human chorionic gonadotropin, tamoxifen, and isotretinoin, to limit testicular atrophy, gynecomastia, and acne, respectively).
Because of constant improvements in drug testing in recent decades, athlete AAS use has shifted from pharmaceutical xenobiotics to T, to prohormones, to designer steroids (developed only to elude anti-doping tests). Meanwhile, AAS use has spread to the general population. Although legitimate uses are mostly limited to treating hypogonadal men (age >50 years) with T, and AAS are controlled substances, they are widely available through antiaging clinics and the Internet. An online search for “buy anabolic steroids” yielded 2.8 million hits in 2013. A 2007 study of 7500 high school girls found a 5% AAS usage rate. Therefore, clinicians need to maintain suspicion for AAS use by a variety of patients in terms of activity, age, and gender.
AAS have been used in cases of severe burns. However, although athletes often claim that they used AAS to assist in injury recovery, there are no human studies to support this, and it is not a legitimate use of AAS.
Adverse effects
Adverse effects of AAS are well described. Physiologic T doses for T replacement are relatively safe, but AAS abusers consume megadoses, risking dose-dependent complications (eg, psychiatric ) and the additive effects of multiple AAS and other doping agents.
Although AAS can affect every bodily system, cardiovascular risks are a major concern. High-dose AAS can increase total cholesterol ; they increase low-density lipoprotein cholesterol and markedly suppress high-density lipoprotein (HDL) cholesterol. One author (G.A.G.) has seen an HDL level of less than 10 mg/dL in users of multiple AAS, especially nandrolone. This level represents a major risk factor for coronary artery disease, and there are case reports of myocardial infarctions even in young bodybuilders. AAS have also been used for anemia. One author (G.A.G.) has seen AAS users with a hemoglobin level greater than 18 g/dL to the point that phlebotomies were required to reduce red cell mass.
Liver damage, particularly with the water-soluble, 17-alkylated oral AAS, is due to first-pass metabolism, and can cause elevated liver function test results, peliosis hepatis, and hepatomas. Therefore, liver function tests and hepatic ultrasonography should be part of the evaluation of an AAS user.
Diffuse acne, especially on the chest and back, occurs so often that AAS users combat it by taking oral isotretinoin. Unusual tendon ruptures (eg, triceps, pectoralis major ) are generally ascribed to muscle strength exceeding tendon tensile strength.
Men who use large AAS doses may overload the liver and aromatize the excess to estrogens, causing gynecomastia. To counteract it, many AAS users also take antiestrogens (eg, clomiphene) or aromatase inhibitors (eg, anastrozole), ie, drugs never used in the treatment of hypogonadism with replacement doses of T. Estrogen may actually play a prominent role in male libido.
Women can suffer loss or alteration of menses and virilization. Deepening of the voice, male pattern alopecia, and clitoromegaly are often irreversible.
Youth can suffer accelerated puberty and stunted growth from epiphyseal closure. Some young men have committed suicide while cycling off AAS.
Risks are heightened when users take AAS never approved for human use, such as boldenone, used in veterinary medicine to treat debilitated horses to increase weight and appetite, and to improve performance. This agent was identified by WADA laboratories in 63 samples in 2012. The risks are most unpredictable with designer steroids (eg, BALCO’s tetrahydrogestrinone).
Enhancement of Oxygen Transfer
Legitimate indications
Recombinant epoetin-α (rHuEPO) is structurally very similar to endogenous erythropoietin (EPO). Darbepoetin-α is a genetically modified EPO with a longer duration of action than epoetin-α. Both are used to treat anemia secondary to chemotherapy, neoplastic disease, and chronic renal failure. Epoetin-α is also approved for use in anemic patients at high risk of blood loss from surgery. It has been used for other conditions associated with anemia. Methoxy polyethylene glycol-epoetin β is a continuous EPO receptor activator (CERA), which can be given once a month and is indicated for the treatment of the anemia of chronic renal failure.
Misuse
Whereas most doping agents have a ceiling effect with respect to performance enhancement, endurance activity is highly dependent on peak oxygen uptake (V o 2max ), which depends on hemoglobin mass. When winners are determined by small percentages of overall race time, a clinically insignificant difference can have significant sports implications.
Before 1987, “blood doping” by transfusion was the mainstay for athletes attempting to increase red cell mass. Risks involved storage issues, transfusion reactions, and infection. The introduction of rHuEPO in 1987 ushered in a new era of doping.
Because rHuEPO is so similar to natural EPO, it took years to develop a urine test. Meanwhile, athletes had unfettered use of rHuEPO, and this led to an “arms race” of elevated hemoglobins. A cluster of up to 20 deaths among Dutch and Belgian cyclists in the late 1980s led to speculation that rHuEPO may have been involved. By 1997, the International Cycling Federation had adopted a health requirement of a hematocrit less than 50% for males (47% for females), a harm-reduction strategy while awaiting a test for rHuEPO, which took until 2000. In 2001, darbepoetin-α was released and a few competitors were caught using it. In 2003, the BALCO scandal showed that rHuEPO was no longer the province of endurance athletes, as it was also given to sprinters. Athletes also turned to some of the proliferating (foreign pharmaceutical or rogue), nearly identical biosimilar EPOs, and got away with it until WADA adapted identification criteria. Next came very-long-acting CERA. Not surprisingly, athletes had also moved back to the use of blood transfusions, and some were caught.
Adverse effects
Serious adverse effects from the therapeutic use of rHuEPO include myocardial infarction and thromboembolic events. This possibility makes the athlete mentality of “if a little is good, then more is better” particularly dangerous when applied to erythropoietic agents, as suggested by the 1980s cluster of cyclist deaths. Although dopers do not publish their findings, one case report on an athlete seems to link rHuEPO to cerebral thrombosis, and athletes using rHuEPO are at risk for iron disorders and exercise-induced elevated systolic pressure.
Growth Hormone
Legitimate indications
By law, recombinant human growth hormone (rhGH), or somatropin, can be prescribed in the United States only for a few conditions including short stature, Turner syndrome, and Prader-Willi syndrome in children, and in adults, growth hormone (GH) deficiency and wasting in AIDS patients.
Misuse
In the United States, the use of rhGH to improve athletic performance, to help with injury recovery, for bodybuilding purposes, and as an antiaging agent are illegal; GH is one of the few drugs that cannot be given legally for off-label indications. Current evidence is vastly insufficient to warrant rhGH use to promote injury healing. However, rhGH is rarely used by itself by antiaging doctors. One author (G.A.G.) has reviewed antiaging clinics cases and has yet to find a case whereby rhGH was not used in combination with AAS. Indeed, 25% of AAS users surveyed admitted to also using rhGH, often in combination with insulin. This finding is consistent with the physiology of hGH, which can become catabolic if not combined with AAS or insulin.
There are no studies demonstrating that hGH alone can increase physical performance in healthy subjects. Reasons for this include underpowered sample sizes, inadequate dosing regimens, and inappropriate subject populations, reminiscent of 1960s AAS research. However, athletes apparently use hGH with AAS, even in low doses of the latter.
Although athletes have been using hGH for many years, its use in the general population far exceeds that of the sports group. United States congressional testimony in 2008 revealed 276 antiaging, rejuvenation, or wellness clinics in the United States that advertised online that they provided hGH, none of which provided legitimate prescriptions. Nevertheless, such clinics have since proliferated. An Internet search for “buy hGH” yielded more than 5 million hits in 2013. In addition, GH-releasing peptides are on the increase.
Adverse effects
Adverse effects of the therapeutic use of hGH include edema, arthralgia, myalgia, antisocial behavior, and depression. Studies of hGH administration in older subjects have documented glucose intolerance, diabetes, and, commonly, carpal tunnel syndrome (caused by median nerve edema). Acromegalics develop a classic coarsening of the bones of the face, hands, and feet. However, acromegalics typically produce slightly increased amounts of GH over many years and may not represent an apt comparison with an athlete on ill-documented high doses over a shorter time, which no ethics committee would approve. Thus, the adverse effects of hGH doping remain difficult to ascertain.
Drug Detection in Doping Control
The periods of detectability by current laboratory tests are shown in Table 2 .
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