The process of phagocytosis (a macrophage consuming a pathogen) in macrophages appears to be associated with an acute reduction in creatine phosphate stores (45%)[436] and an increase in creatine kinase activity,[290] although prolonged stimulation is met with an increase in creatine phosphate (20%).[290] The creatine kinase activity does not appear to be altered based on creatine availability,[290] but since ATP seems to be preserved in these instances,[436][290] the increase in phosphocreatine may be explained by an overall creatine pool paralleling that found in medium.[290]

I get lost every time I walk into my neighborhood GNC… the people who work there know their stuff, but nobody knows my body better than me and that’s where it all falls apart, but I’m working on that. I agree, I rather have grass-fed and more natural options as opposed to anything containing GMO in the products… The point is to become healthier, not go the other way…. But I also don’t want to get too much soy in my diet either… My wife is doesn’t want it for me and it’s given me headaches too, so I’m not really one for those. I guess small amounts of soy should be okay, right? Could someone be allergic to soy? There’s tons of other options though and I’m going to have to really look more into these here coz it has everything I’ve been looking for! Thanks for putting this together! 

In young rats given creatine in the diet at 2% of the diet for eight weeks, supplementation appears to increase bone mineral density (BMD) in the lumbar spine with a nonsignificant trend to increase BMD in the femur.[426] Despite the trend, the femur appeared to be 12.3% more resistant to snapping from mechanical stress associated with increased thickness.[426] Menopausal rats (ovarectomized) experience similar benefits, as supplementation of creatine (300mg/kg) for eight weeks during ovarectomy is able to increase phosphorus content of the bone and other biomarkers of bone health, although bone stress resistance was not tested.[427]
Arguably the most influential factor, exercise is what instigates muscle growth. When you exercise, especially if you engage in resistance training, it causes trauma to your muscles. This is exactly what you want because it’s this trauma that triggers a response from your body that grows your muscles. To repair the injury or damage to your muscles, special cells called satellite cells arrive. Typically, your muscle fibers thicken and lengthen in this process. (1)
Every gym has a guy shaped like a lightbulb. He's the one who neglects his lower body. If you don't want to be that guy, work your major leg muscles on the leg press machine. Place your feet on the plate with knees bent at 90 degrees. Grasp the handles and slowly push the plate out until your knees are straight but not locked. Pause and slowly return to the starting spot.
Dymatize Nutrition maximizes the benefits of protein in ISO-100 through its use of hydrolyzed 100% whey protein isolate. Designed to increase the absorption of protein, this fast-acting protein provides 25 grams of protein and 5.5 grams of BCAAs per serving, with no gluten or lactose. With a formula that aids in the instantaneous delivery of effective and advanced protein forms straight to the muscle, ISO-100 is able to repair and build muscle faster, resulting in the ability to reach fitness goals sooner rather than later. Keep Reading »
It can be hard to know where to start when beginning strength training. There are countless exercises you can do, some of which work some muscles, but not others. There are safety concerns to beware of, a wide variety of sometimes confusing equipment to help you in your efforts, and so on. With some familiarity of the basics of getting started with strength training, actually doing so can become far less daunting, and you can begin to craft a routine that is targeted toward helping you achieve your personal goals.
Overload: The first thing you need to do to build lean muscle tissue is use more resistance than your muscles are used to. This is important because the more you do, the more your body is capable of doing, so you should increase your workload to avoid plateaus. In plain language, this means you should be lifting enough weight that you can only complete the desired number of reps. You should be able to finish your last rep with difficulty, but also with good form.
The first open label trial on ALS failed to significantly alter lung function as assessed by FEV (when comparing the rate of decline pretreatment relative to treatment).[545] Creatine has elsewhere failed to benefit lung function at 5g daily for months relative to control[546] and failed to significantly attenuate the rate of lung function deterioration over 16 months at 10g daily[505] and 5g daily over nine months.[507]
^ Jump up to: a b c d e f g h Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Med. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250. Wilson et al. [91] demonstrated that when non-resistance trained males received HMB pre-exercise, the rise of lactate dehydrogenase (LDH) levels reduced, and HMB tended to decrease soreness. Knitter et al. [92] showed a decrease in LDH and creatine phosphokinase (CPK), a byproduct of muscle breakdown, by HMB after a prolonged run. ... The utility of HMB does seem to be affected by timing of intake prior to workouts and dosage [97].
In the stomach, creatine can degrade by about 13% due to the digestive hormone pepsin, as assessed by simulated digestion.[127] Although creatinine is a known byproduct of creatine degradation, simulated gastric digestion did not increase creatinine levels, indicating that other breakdown products were formed. However, creatinine was noted to increase in the presence of pancreatin, a mixture of pancreatic enzymes.[127] 
Deldicque et al [32] found a 250%, 45% and 70% increase for collagen mRNA, glucose transporter 4 (GLUT4) and Myosin heavy chain IIA, respectively after 5 days creatine loading protocol (21 g/d). The authors speculated that creatine in addition to a single bout of resistance training can favor an anabolic environment by inducing changes in gene expression after only 5 days of supplementation.
Vegetarians and other people who have lower total creatine levels when they start taking creatine supplements seem to get more benefit than people who start with a higher level of creatine. Skeletal muscle will only hold a certain amount of creatine; adding more won't raise levels any more. This "saturation point" is usually reached within the first few days of taking a "loading dose."
Han:SPRD‐cy rats (human polycystic kidney disease model[514][515]) have pre-existing renal damage, which is accelerated upon ingestion of creatine supplementation at 0.3% of the diet for five days and 0.03-0.05% for the next 35 days (equivalent to human loading and maintenance).[516] During this particular disease state, renal water content and size progressively increases.[514][515] Since creatine supplementation furthered the increase by an additional 2.1%, it was thought that this property of creatine explained the 23% increased cyst scores seen relative to control.[516]
There is a great amount of research published on creatine supplementation; protocols of administration, forms of creatine, as well as potential side effects. Despite this, the mechanisms by which creatine acts in the human body to improve physical and cognitive performance are still not clear. The main objectives of this review are to analyze the more recent findings on the effects and mechanisms of creatine supplementation in sports and health. As a secondary purpose, we will analyze the most recommended protocols of ingestion and its potential side effects.
Guanidoacetate (made by AGAT) then receives a methyl donation from S-adenosyl methionine via the enzyme guanidinoacetate methyltransferase (GAMT), which produces S-adenosylhomocysteine (as a byproduct) and creatine. Deficiencies in GAMT are more severe (although equally rare) relative to AGAT, resulting in severe mental retardation and autism-like symptoms.[31]
Contrary to the sound of the name, glucosamine is not a glucose replacement drink but a naturally occurring compound that has received publicity and wide support as a supplement for the relief of arthritis pain and possible prevention of further joint damage. Glucosamine has been popular with sports people of all types, including weight trainers, particularly for knee arthritis and pain. Glucosamine seems to be safe to use.
The neuroprotective effects of creatine appear to exist in regard to dopamine biosynthesis, and the suppression of dopamine synthesis seen with some neurological toxins appears to be partially attenuated with dietary intake of creatine. The protective effect is weak to moderate in animal research, but appears to be additive with anti-inflammatories.
Previous investigations have shown that a single dose of CM (8 grams) increased the number of repetitions performed during an upper-body resistance training protocol and reduced soreness at 24 and 48 hours post-exercise (compared to a placebo).7 Recently, researchers from Mississippi State University found that a single dose of CM (8 grams) significantly increased the number of lower-body repetitions compared to a placebo group.[8]
Contrast loading is the alternation of heavy and light loads. Considered as sets, the heavy load is performed at about 85-95% 1 repetition max; the light load should be considerably lighter at about 30-60% 1RM. Both sets should be performed fast with the lighter set being performed as fast as possible. The joints should not be locked as this inhibits muscle fibre recruitment and reduces the speed at which the exercise can be performed. The lighter set may be a loaded plyometric exercise such as loaded squat jumps or jumps with a trap bar.

What kind of exercises? Work all major muscle groups, starting with the larger muscles. Always include exercises for opposing muscles: for example, work the biceps and triceps of your arms, and the quadriceps and hamstrings of your thighs. Avoid above-the-shoulder exercises if you have arthritis in your upper body, and talk to your doctor before using leg press machines if you have arthritis in your knees or hips.
Most experts recommend starting with your larger muscle groups and then proceeding to the smaller muscle groups. The most demanding exercises are those performed by your large muscle groups and you will need your smaller muscles to get the most out of these exercises. But, don't feel limited by that. You can do your exercises in any order you like and changing the order is a great way to challenge yourself in different ways.
According to research from the University of Stirling, for optimal protein growth, weight lifters need to eat 0.25 to 0.30 grams of protein per kilogram body weight per meal. For a 175-pound person, that works out to 20 to 24 grams of protein at every meal. You’ll get that in three to four eggs, a cup of Greek yogurt, or one scoop of protein powder.
Most experts recommend starting with your larger muscle groups and then proceeding to the smaller muscle groups. The most demanding exercises are those performed by your large muscle groups and you will need your smaller muscles to get the most out of these exercises. But, don't feel limited by that. You can do your exercises in any order you like and changing the order is a great way to challenge yourself in different ways.

Although creatine is a natural component of food, the amount of food required to supersaturate the muscle with PCr may not be feasible. For example, it could require 22 pounds of meat daily [8]. If creatine monohydrate is proven to be a safe and effective ergogenic aid, creatine supplementation may be the simplest way to increasing muscle stores. It may be beneficial to avoid caffeine if taking creatine supplements. One study showed that caffeine diminished strength gains seen with creatine use [9].


When looking specifically at human studies, there has been a failure of creatine supplementation to induce or exacerbate kidney damage in people with amyotrophic lateral sclerosis (ALS). Subjects do not experience kidney damage for up to or over a year’s worth of supplementation in the 5-10g range.[505][506][507] Postmenopausal women,[517] people with type II diabetes,[518] people on hemodialysis,[313] otherwise healthy elderly,[519] young people,[454][520][521] and athletes do not experience kidney damage either.[324] Moreover, numerous scientific reviews on both the long- and short-term safety of supplemental creatine have consistently found no adverse effects on kidney function in a wide range of doses.[522][523][524][452][525][451][526][527] However, while doses >10 g/day have been found not to impair kidney function, there are fewer long-term trials using such high chronic daily intakes.[527]

Previous investigations have shown that a single dose of CM (8 grams) increased the number of repetitions performed during an upper-body resistance training protocol and reduced soreness at 24 and 48 hours post-exercise (compared to a placebo).7 Recently, researchers from Mississippi State University found that a single dose of CM (8 grams) significantly increased the number of lower-body repetitions compared to a placebo group.[8]
It was later noted that creatine was able to nonsignificantly augment various proinflammatory cytokines (CCL2, iNOS, ICAM-1, TGF-β, TIMP-1) and the presence of eosinophils in lung tissue, as well as to per se cause lung infiltration of these immune cells without requiring the presence of the allergen.[442] Neutrophils and macrophages were unaffected,[442] reflecting the past study of no influence on macrophages,[440] but the only instance where creatine appeared to either significantly add to ovalbumin or to per se induce statistically significant increases were in IL-5 secretion and goblet cell infiltration, although VCAM-1 expression was close. While creatine per se increased nF-κB activity, it suppressed the ovalbumin-induced increase.[442]

Before getting into the nitty-gritty details about supplements, it’s important to have a good understanding of how muscle growth works. When you take a muscle growth supplement, the role it plays in helping you reach your goals should be very clear. With the supplements available on the market, you can be sure that while some serve an important purpose, others are gimmicks. It’s easier to identify the money wasters if you know how muscle building works.

Other supplements could easily have been included here, but these are considered the most useful and effective for the majority of bodybuilders and athletes. Although food should always come first, supplements offer an effective alternative for getting nutrients that either aren't available in sufficient quantity in food or are in foods that you may not be eating.


However, protein isn’t everything. Contrary to popular belief, carbohydrates and calories from fats are also important. To gain muscle, people who are slender or scrawny need to create a calorie surplus in order to bulk up. That means you need proteins and plenty of healthy carbs, vegetables and even some fats (think healthy fats like nuts, avocado, olive oil, etc.). Carbohydrates play a key role in building muscle. This macronutrient has gotten a bad rap for making people fat. However, if you work out properly, eating plenty of carbs is in your best interest. After training, it’s ideal to ingest some carbs in combination with protein to help replenish your muscles’ glycogen stores.


There you have it — our five favorite creatine products on the market. But when you’ve tried as many creatines as we have, there were a lot of others that we loved but didn’t make the very top of our list for the previous categories. That’s why we’ve also come up with a list of the best creatines for men, best creatines for women, best creatines for muscle growth, for bulking, for the brain, and the best micronized creatine. Keep reading for our favorite picks!

JAK2 (Janus-Activating Kinase 2) is a novel protein that has been shown to suppress the activity of the creatine transporter CrT in vitro. The effects of JAK2 on CrT are not well-understood in vivo, however. Given that growth hormone activates both c-src (increases CrT activity) and JAK2- which has been found to decrease CrT activity, it is plausible that JAK2 may function as a negative-feedback regulator of creatine uptake. Future research is needed to better understand the role of JAK2 on CrT activity in vivo.

In isolated striatal cells (expressing creatine kinase), seven day incubation of 5mM creatine (maximal effective dose) appears to increase the density of GABAergic neurons and DARPP-32 (biomarker for spiny neurons[225]) with only a minor overall trend for all cells[226] and showed increased GABA uptake into these cells, as well as providing protection against oxygen and glucose deprivation.[226]


McArdle’s disease is a myopathic disorder associated with fatigue and contractile dysfunction as a result of alterations in the release of glucose from glycogen (via defects in myophosphorylase enzyme function) resulting in an inability to conduct high intensity work as easily.[548] Creatine is thought to be therapeutic because beyond the general strength enhancing properties of creatine, people with McArdle’s disease have an upregulation of phosphofructokinase (PFK) enzyme activity [570] and increasing phosphocreatine storages suppresses the activity of this enzyme.[571]

References to any non-Onnit entity, product, service, person or source of information in this or any other Communication should not be considered an endorsement, either direct or implied, by the host, presenter or distributor of the Communication. The host(s), presenter(s) and/or distributor(s) of this Communication are not responsible for the content of any non-Onnit internet pages referenced in the Communication. Onnit is not liable or responsible for any advice, course of treatment, diagnosis or any other information or services you chose to follow without consulting a qualified medical professional. Before starting any new diet and/or exercise program, always be sure to check with your qualified medical professional.
Another favorite bodybuilding supplement, creatine is an amino acid found in the body. The highest levels of this molecule are in your muscles and brain. It is made by your liver, pancreas and kidneys, but is also found in foods including meat, eggs and fish. Research has shown that it may help athletes including weightlifters who need short bursts of energy (5). In this study, creatine monohydrate proved to be an effective muscle builder. It works to improve body composition, muscle mass, strength and power.  Note that it was also more effective than other forms of creatine. How does it do this?
Taking creatine supplements may increase the amount of creatine in the muscles. Muscles may be able to generate more energy or generate energy at a faster rate. Some people think that taking creatine supplements along with training will improve performance by providing quick bursts of intense energy for activities such as sprinting and weightlifting.

When it comes to building muscle, your body only knows or cares about the tension, fatigue and damage an exercise is generating… not the type of equipment you were using when performing that exercise. It really couldn’t give the slightest crap about that. For this reason, ALL types of exercises and ALL types of equipment are capable of stimulating muscle growth.

While some supplements may in fact provide health benefits, generally speaking, consumers should purchase and use these products cautiously as they are not closely regulated by the Food and Drug Administration (FDA). Also, bodybuilders are advised to discuss supplementation plans with a registered dietitian or primary care physician prior to use to optimize effectiveness and minimize potential harmful consequences. 

It has also been noted that supplementing creatine (which reduces internal synthesis of creatine and methylation requirements) preserved folate and tetrahydrofolate status (42% and 23%),[312] which acted to preserve methyl groups for other processes. Despite this effect, global DNA methylation decreases by 22% (assessed by the 5-methylcytosine/cytosine ratio) following creatine supplementation, which is usually seen as an anti-cancer effect in developed mammals.[461] This study was unable to demonstrate why this reduction occured[461] and opposing effects have been noted in females with Rett syndrome supplementing 200mg/kg creatine for 1 year, during which global methylation increased, secondary to preserving other methyl donors.[462]
Genetic deficiencies in the creatine biosynthetic pathway lead to various severe neurological defects.[26] Clinically, there are three distinct disorders of creatine metabolism. Deficiencies in the two synthesis enzymes can cause L-arginine:glycine amidinotransferase deficiency caused by variants in GATM and guanidinoacetate methyltransferase deficiency, caused by variants in GAMT. Both biosynthetic defects are inherited in an autosomal recessive manner. A third defect, creatine transporter defect, is caused by mutations in SLC6A8 and inherited in a X-linked manner. This condition is related to the transport of creatine into the brain.[27]
Liquid creatine has been shown to be less effective than creatine monohydrate.[69] This reduced effect is due to the passive breakdown of creatine over a period of days into creatinine, which occurs when it is suspended in solution.[70] This breakdown is not an issue for at-home use when creatine is added to shakes, but it is a concern from a manufacturing perspective in regard to shelf-life before use.

Recommended dose: The fastest way to increase muscle creatine stores is to follow the loading method of 20 grams per day for 5-7 days, followed by the standard maintenance dose of 5 grams per day. However, a lower dose of 5 grams for 28 days will also increase creatine stores without causing the 2-4 pound weight gain typically seen with a loading protocol.

Most folks work a 9 to 5 position but if you’re not in the corporate world yet then odds are you’re a student with classes scattered throughout the day and it takes up the vast portion of your free time. That being said, you’re likely going to have to work out in the morning or the evening in order to fit in your session amidst the hectic commitments in your everyday life. Here are a few things to consider in regards to each time period:
Supplementation of a loading phase of creatine has been noted to augment the increase in RBC levels of superoxide dismutase (SOD) from exercise, when measured immediately after, by 8.1%, but control groups increased to match within an hour.[299] Glutathione (normally decreases with exercise) and catalase (increases) were both unaffected,[299] and elsewhere in vitro red blood cells incubated with 3mM of creatine (within the supplemental range) is able to improve filterability (a measure of cell rheology, or fluid structure of the cell[300]) when RBC creatine was increased by 12.3% to reach 554µM.[301] This was thought to be due to reduced oxidative stress (assessed via MDA) in the red blood cells, which in the presence of 1-5mM creatine was progressively reduced by 20-41%.[301]

Weight training is a common type of strength training for developing the strength and size of skeletal muscles. It utilizes the force of gravity in the form of weighted bars, dumbbells or weight stacks in order to oppose the force generated by muscle through concentric or eccentric contraction. Weight training uses a variety of specialized equipment to target specific muscle groups and types of movement.

At the same time, this also doesn’t mean that primary compound exercises can never be done for more than 8 reps, or that secondary compound exercise can’t be done for 5-8 or 10-15 reps, or that isolation exercises can’t be done for less than 10 reps. Everything can be done in every rep range. However, these are the rep ranges that each type of exercise is best suited for, and where it should ideally be done most of the time.
Endurance exercise is also known to produce heat from skeletal muscle tissue, and an increase in internal temperature occurs when the production of heat (from metabolism) exceeds release. This increase in heat is accelerated when training in hot environments[390] and it is thought to be beneficial to retain water (hydration) during exercise, since more water allows a preservation of plasma volume (PV) and the sweat response reduces internal temperature.[391][392] This particular phenomena may only apply to endurance exercise, since creatine is able to increase sprint performance in heat, independent of altering the decline in PV and sweat rates.[393]
When looking for a whey protein powder to purchase, seek out powders that offer at least 20 g of protein per serving (one scoop) and are low in carbohydrates (aim for 5 g per serving or less). You may run into whey protein isolate, which looks attractive because it’s a higher concentration of protein. However, avoid this one as in the extreme processing, proteins are denatured that can render them less effective. In addition, these formulas are also often chock full of artificial sweeteners. Instead, look for powders from grass-fed cows that aren’t pumped with hormones.
Maintaining proper form is one of the many steps in order to perfectly perform a certain technique. Correct form in weight training improves strength, muscle tone, and maintaining a healthy weight. Proper form will prevent any strains or fractures.[6] When the exercise becomes difficult towards the end of a set, there is a temptation to cheat, i.e., to use poor form to recruit other muscle groups to assist the effort. Avoid heavy weight and keep the number of repetitions to a minimum. This may shift the effort to weaker muscles that cannot handle the weight. For example, the squat and the deadlift are used to exercise the largest muscles in the body—the leg and buttock muscles—so they require substantial weight. Beginners are tempted to round their back while performing these exercises. The relaxation of the spinal erectors which allows the lower back to round can cause shearing in the vertebrae of the lumbar spine, potentially damaging the spinal discs.
*Always remember: weight loss results & health changes/improvements vary from individual to individual. Just because these studies cite certain data does not mean you will experience these results/outcomes. Always consult with your doctor before making decisions about your health. This is not medical advice – simply well-researched information and tips to sleep better. Thanks for reading!
^ Jump up to: a b c d e Cooper R, Naclerio F, Allgrove J, Jimenez A (July 2012). "Creatine supplementation with specific view to exercise/sports performance: an update". Journal of the International Society of Sports Nutrition. 9 (1): 33. doi:10.1186/1550-2783-9-33. PMC 3407788. PMID 22817979. Creatine is produced endogenously at an amount of about 1 g/d. Synthesis predominately occurs in the liver, kidneys, and to a lesser extent in the pancreas. The remainder of the creatine available to the body is obtained through the diet at about 1 g/d for an omnivorous diet. 95% of the bodies creatine stores are found in the skeletal muscle and the remaining 5% is distributed in the brain, liver, kidney, and testes [1].

Still, any supplement should be used carefully and after discussion with a dietitian or doctor. There are some potential health risks and side effects that you should be aware of before taking creatine. Muscle cramping, nausea, diarrhea, dizziness, gastrointestinal pain, dehydration, weight gain, water retention, heat intolerance, and fever have all been linked to the supplement. (13)

Creatine Ethyl Ester, or CEE for short, is a powdered form of creatine which has an ethyl group attached to the creatine. This is said to make the creatine more easily absorbed in the human body which would allow you to benefit the most. The studies have not been entirely conclusive as to whether CEE is better than creatine monohydrate. Since Creatine monohydrate is the single most researched form of creatine, it is


Creatine is vital for brain function, which has mechanisms to take up creatine, as well as regulate its intake. Although the diet appears to be the major source of creatine (and thus lack of dietary intake could cause a non-clinical deficiency) excess levels of creatine do not appear to “super-load” the brain similar to muscle tissue. Due to kinetics, creatine appears to be more “preventative” or acts to restore a deficiency in the brain. This is in contrast to creatine effects in muscle cells, where it can affect performance substantially on an acute timescale.

Some bodybuilders use drugs such as anabolic steroids and precursor substances such as prohormones to increase muscle hypertrophy. Anabolic steroids cause hypertrophy of both types (I and II) of muscle fibers, likely caused by an increased synthesis of muscle proteins. They also provoke undesired side effects including hepatotoxicity, gynecomastia, acne, the early onset of male pattern baldness and a decline in the body's own testosterone production, which can cause testicular atrophy.[42][43][44] Other performance-enhancing substances used by competitive bodybuilders include human growth hormone (HGH), which can cause acromegaly.
Recommended Dose: 3-6 grams before or during exercise. A ratio of two parts leucine to one part each of isoleucine and valine appears to be most beneficial. As Krissy Kendall, PhD, explains in "The Top 7 Supplements to Boost Endurance Performance," BCAAs can be just as effective for endurance athletes like runners, rowers, and cyclists as they can be for lifters and bodybuilders. 

4. Focus on a full range of motion. Moving as far as anatomically possible – for example, in a squat, lowering as low as you can without breaking form – is critical to maximize muscle adaptation, rather than partials or cutting the range of motion short, according to a 2017 study in the Journal of Strength and Conditioning Research. And while partials do have their time and place, and can be part of a muscle-building plan, the majority of your exercises should still prioritize a full range of motion, Matheny says.
Synthesis primarily takes place in the kidney and liver, with creatine then being transported to the muscles via the blood. The majority of the human body's total creatine and phosphocreatine stores is located in skeletal muscle, while the remainder is distributed in the blood, brain, and other tissues.[17][18][20] Typically, creatine is produced endogenously at an estimated rate of about 8.3 mmol or 1 gram per day in young adults.[16][17] Creatine is also obtained through the diet at a rate of about 1 gram per day from an omnivorous diet.[17][18] Some small studies suggest that total muscle creatine is significantly lower in vegetarians than non-vegetarians, as expected since foods of animal origin are the primary source of creatine. However, subjects happened to show the same levels after using supplements.[21]
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