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  1. #1
    Senior Member Ex Dubio's Avatar
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    This drug has come up before on M&M, but some recent studies have considerably added to the amount of data available on the drug.

    First of all, pramipexole is a non-ergoline dopamine D2/D3 agonist. It does not have the heart valve damage issues that its cousins cabergoline (Dostinex) and bromocriptine have. It also displays, somewhat interestingly, a higher affinity for D3 than D2, in contrast to bromocriptine (almost purely D2) and cabergoline (mixed D1/D2). It's Rx (non-scheduled) in the U.S., and studies are appearing about the drug at an impressive rate.

    From personal experience, it has remarkable libido- and erection-improving capabilities and may indeed have some antidepressant properties, though I'm still testing the drug myself.

    At any rate, the following make for some very interesting reading.

    Major Depression In (PMID 10812530), (PMID 12479663), (PMID 15219473), and (PMID 14992985) pramipexole was tested as a lone antidepressant (first study), as an adjunct to an antidepressant (second study), or as an adjunct to a mood stabilizer (third and fourth studies). In all four, it showed considerable efficacy in major depression or bipolar depression. The first is probably most interesting, as it showed (relatively) high-dose pramipexole alone may be as effective as fluoxetine in the treatment of MDD.

    Synergy With SSRIs In (PMID 16963794), data suggests that not only is pramipexole effective as an antidepressant, but it may actually synergize with SSRIs (at least setraline and fluoxetine) in a fairly interesting way. (See the study for details.)

    Mechanism The study (PMID 18688211), though in rats, is probably the most interesting I've found. I'm going to simply quote the last portion of the abstract:

    <div class='quotetop'>QUOTE </div><div class='quotemain'>After 14 days of PPX treatment, the firing rate of DA had recovered as well as that of NE, whereas the firing rate of 5-HT neurons was increased by 38%. It was also observed that sustained PPX administration produced desensitization of D(2)/D(3) and 5-HT(1A) cell body autoreceptors, as well as a decrease in sensitivity of alpha(2)-adrenergic cell body autoreceptors. These adaptive changes are implicated in long-term firing rate adaptations of DA, NE and 5-HT neurons after prolonged PPX administration. In conclusion, the therapeutic action of PPX in depression might be attributed to increased DA and 5-HT neurotransmission.</div>

    In short, though pramipexole is a D2/D3 agonist, it rather dramatically increased the firing rate of 5-HT neurons and desensitized 5-HT(1A) and D2/D3 autoreceptors. The implication is that it should, with chronic use, improve D2 and 5-HT1A sensitivity and increase 5-HT neurotransmission. As all three of these factors have been implicated in major depression (among other psychiatric disorders), this seems absolutely enormous. And note that this study is from 2009, so it's implications have not yet filtered out.

    This is pretty cool stuff. If it pans out, antidepressant sexual side effects may mean something very different a few years down the line...

    EDIT: One last rather important detail. If you read the drug's entry on rxlist.com, it does not have many serious side effects, especially when the dose is titrated appropriately. (If you're going to try the drug, you really have to start at 0.25-0.5mg 2x/day and move up from there.) From personal experience, I got a little orthostatic hypotension, a little fatigue, and a little nausea at the start, but with continued treatment they went away. The last study in mice supports this - NE function declines initially, but recovers with chronic treatment. Fucking awesome.

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    Senior Member DavidWebb's Avatar
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    My legs are feeling restless already. I'm going to probably get an rx for this and I'll post up the results.

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    I've got some on the way, should be here by the end of the week. I'm looking forward to trying this with high hopes. I don't have much experience with D receptor agonists outside of a short bromocriptine trial which I did not tolerate well at all. I'm looking to use it for mood and libido.

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    Senior Member The450Man's Avatar
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    hypersexuality is one of the side effects [img]style_emoticons/<#EMO_DIR#>/smile.gif[/img]

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    Senior Member DavidWebb's Avatar
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    <div class='quotetop'>QUOTE (The450Man @ Mar 18 2009, 02:16 AM) <{POST_SNAPBACK}></div><div class='quotemain'>hypersexuality is one of the side effects [img]style_emoticons/<#EMO_DIR#>/smile.gif[/img]</div>

    you forgot to also mention compulsive gambling, excessive shopping, binge eating, and cross dressing.

    oh yeah and sleep attacks too.

    just imagine what craziness the seniors at the parkinsons studies got into. [img]style_emoticons/<#EMO_DIR#>/ohmy.gif[/img]

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    <div class='quotetop'>QUOTE (DavidWebb @ Mar 17 2009, 11:45 PM) <{POST_SNAPBACK}></div><div class='quotemain'>you forgot to also mention compulsive gambling, excessive shopping, binge eating, and cross dressing.

    oh yeah and sleep attacks too.

    just imagine what craziness the seniors at the parkinsons studies got into. [img]style_emoticons/<#EMO_DIR#>/ohmy.gif[/img]</div>

    Yeah alot of lawsuits over this.

    The horrors of excess dopamine is exhibited all Neuroscience forum ("MOAR ADDERALL") [img]style_emoticons/<#EMO_DIR#>/laugh.gif[/img]


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    Senior Member Ex Dubio's Avatar
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    <div class='quotetop'>QUOTE (avantgarde @ Mar 18 2009, 12:57 AM) <{POST_SNAPBACK}></div><div class='quotemain'>Yeah alot of lawsuits over this.

    The horrors of excess dopamine is exhibited all Neuroscience forum ("MOAR ADDERALL") [img]style_emoticons/<#EMO_DIR#>/laugh.gif[/img]</div>

    While perhaps severe, the prevalence of these types of behaviors in the studies is very, very low. Hypersexuality makes a fair amount of sense (just try this stuff, even at 0.25mg 2x/day...), but the rest only makes sense with some degree of pre-existing psychological disorder or penchant for abnormal activity. D3 does to some degree reduce the activity of D2, leading to impulse inhibition, but at lower doses in individuals without OCD or impulsive behavior, I suspect the side effects should be minimal.

    About the only near-impulsive behavior I've seen is purely sexual in nature and would be expected to accompany a ridiculous increase in libido.

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    Senior Member DavidWebb's Avatar
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    <div class='quotetop'>QUOTE (Ex Dubio @ Mar 18 2009, 08:51 PM) <{POST_SNAPBACK}></div><div class='quotemain'>About the only near-impulsive behavior I've seen is purely sexual in nature and would be expected to accompany a ridiculous increase in libido.</div>

    is this partially a result of increased test perhaps?

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    Senior Member Ex Dubio's Avatar
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    <div class='quotetop'>QUOTE (DavidWebb @ Mar 18 2009, 05:54 PM) <{POST_SNAPBACK}></div><div class='quotemain'>is this partially a result of increased test perhaps?</div>

    I can guarantee you it's not anecdotally, as I'm on TRT.

    More specifically (I don't have cites on hand, but bear with me), D2/D3 agonism (they're interlinked, in a way) increases hypothalamic oxytocin, which mediates erections. I haven't looked into this recently, but I'm pretty sure hypothalamic oxytocin also increases sexual drive and interest. If I'm wrong about that, then D2 in another part of the brain is responsible for it.

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    Bump. Any further feedback on pramipexole?

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    <div class='quotetop'>QUOTE (Ex Dubio @ Mar 17 2009, 02:07 PM) <{POST_SNAPBACK}></div><div class='quotemain'>This drug has come up before on M&M, but some recent studies have considerably added to the amount of data available on the drug.

    First of all, pramipexole is a non-ergoline dopamine D2/D3 agonist. It does not have the heart valve damage issues that its cousins cabergoline (Dostinex) and bromocriptine have. It also displays, somewhat interestingly, a higher affinity for D3 than D2, in contrast to bromocriptine (almost purely D2) and cabergoline (mixed D1/D2). It's Rx (non-scheduled) in the U.S., and studies are appearing about the drug at an impressive rate.

    From personal experience, it has remarkable libido- and erection-improving capabilities and may indeed have some antidepressant properties, though I'm still testing the drug myself.

    At any rate, the following make for some very interesting reading.

    Major Depression In (PMID 10812530), (PMID 12479663), (PMID 15219473), and (PMID 14992985) pramipexole was tested as a lone antidepressant (first study), as an adjunct to an antidepressant (second study), or as an adjunct to a mood stabilizer (third and fourth studies). In all four, it showed considerable efficacy in major depression or bipolar depression. The first is probably most interesting, as it showed (relatively) high-dose pramipexole alone may be as effective as fluoxetine in the treatment of MDD.

    Synergy With SSRIs In (PMID 16963794), data suggests that not only is pramipexole effective as an antidepressant, but it may actually synergize with SSRIs (at least setraline and fluoxetine) in a fairly interesting way. (See the study for details.)

    Mechanism The study (PMID 18688211), though in rats, is probably the most interesting I've found. I'm going to simply quote the last portion of the abstract:



    In short, though pramipexole is a D2/D3 agonist, it rather dramatically increased the firing rate of 5-HT neurons and desensitized 5-HT(1A) and D2/D3 autoreceptors. The implication is that it should, with chronic use, improve D2 and 5-HT1A sensitivity and increase 5-HT neurotransmission. As all three of these factors have been implicated in major depression (among other psychiatric disorders), this seems absolutely enormous. And note that this study is from 2009, so it's implications have not yet filtered out.

    This is pretty cool stuff. If it pans out, antidepressant sexual side effects may mean something very different a few years down the line...

    EDIT: One last rather important detail. If you read the drug's entry on rxlist.com, it does not have many serious side effects, especially when the dose is titrated appropriately. (If you're going to try the drug, you really have to start at 0.25-0.5mg 2x/day and move up from there.) From personal experience, I got a little orthostatic hypotension, a little fatigue, and a little nausea at the start, but with continued treatment they went away. The last study in mice supports this - NE function declines initially, but recovers with chronic treatment. Fucking awesome.</div>

    Have you noticed any differences (improvement) in body composition from pramipexole, such as bromocriptine was supposed to?

    Thanks.



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    I've been on it for oh...4 days now and so far no good for me. I'm tolerating it far better than I did bromocriptine it is essentially side effect free save for some pretty bad somnolence and strangely enough insomnia at the same time at only .25mgs a day. I've tried taking it at night and it sedates me but also speeds me up a little and makes it damn near impossible to sleep. When I take it in the morning I feel dopey and out of it and yawn all the time. Pretty damn strange overall and I guess I'm going to abandon my trial since I can't function at work on no sleep or feeling stoned. There are some pretty good anecdotal reports on the net about this stuff so I'm either a weird outlier, a pussy or both. [img]style_emoticons/<#EMO_DIR#>/huh.gif[/img]

    I remember reading loki's pergolide articles and I have no idea how he managed to tolerate that stuff.

  13. #13
    Senior Member FunkOdyssey's Avatar
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    I'm going to mess with this a little. I had some good times with cabergoline but I was scared off by heart valve concerns.

    What dose have you settled on Ex Dubio? How long did it take NE function to recover (as measured by fatigue, hypotension, etc) after initiating therapy?
    "Also, can I rig some sort of enema out of household items?" -Tussman

    "I don't have the stamina for a 3-some, and I am a one-pump chump" -Ubiyca

  14. #14
    Senior Member Jakeshorts's Avatar
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    <div class='quotetop'>QUOTE (bdog527 @ Mar 24 2009, 12:02 PM) <{POST_SNAPBACK}></div><div class='quotemain'>I've been on it for oh...4 days now and so far no good for me. I'm tolerating it far better than I did bromocriptine it is essentially side effect free save for some pretty bad somnolence and strangely enough insomnia at the same time at only .25mgs a day. I've tried taking it at night and it sedates me but also speeds me up a little and makes it damn near impossible to sleep. When I take it in the morning I feel dopey and out of it and yawn all the time. Pretty damn strange overall and I guess I'm going to abandon my trial since I can't function at work on no sleep or feeling stoned. There are some pretty good anecdotal reports on the net about this stuff so I'm either a weird outlier, a pussy or both. [img]style_emoticons/<#EMO_DIR#>/huh.gif[/img]

    I remember reading loki's pergolide articles and I have no idea how he managed to tolerate that stuff.</div>

    Loki's article on pergolide is unreal. I think in one instance he passed out in them middle of campus. After taking bromo I can understand how it could happen.

    ftr - I think bromo's body composition effects were through D1 stimulation, and manifested itself via appetite suppression largely.

    As for this business, I'd say titrating on and off would be requisit. Be careful. If you already have high D levels and take a high dose of this stuff you could wake up in the middle of city hall naked as a jay bird.
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  15. #15
    Senior Member Ex Dubio's Avatar
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    <div class='quotetop'>QUOTE (AlbaGuBrath @ Mar 24 2009, 04:15 AM) <{POST_SNAPBACK}></div><div class='quotemain'>Have you noticed any differences (improvement) in body composition from pramipexole, such as bromocriptine was supposed to?

    Thanks.</div>

    Though I own Lyle's book, took Bromo back in the day, and have a great deal of faith in the man's reasoning and analytical ability, I was never convinced, anecdotally or theoretically, that bromocriptine would actually improve body composition in a healthy male.

    After trying it repeatedly at doses from 2.5mg-10mg, I never really got anything out of it in that respect. The research shows benefit in postmenopausal women, but was never proven outside of mouse studies otherwise. Given the enormous effects of estrogen on brain function and metabolism, I never quite bought using postmenopausal women as a test paradigm. There are some very convincing studies in rodents, but as we all know, it's no challenge to make a rodent lose weight.

    At any rate, I wouldn't bet on using pramipexole for body composition. It certainly wouldn't be expected to be much superior to bromocriptine, and the user reports there were never as positive as the data suggested, sadly.

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    Senior Member FunkOdyssey's Avatar
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    <div class='quotetop'>QUOTE </div><div class='quotemain'>Antidepressant effects of dopamine agonists :
    Experimental and clinical findings
    by
    Lemke MR.
    Rheinische Kliniken Bonn, Kaiser-Karl-Ring 20,
    53111, Bonn, Deutschland,
    mr.lemke@lvr.de.
    Nervenarzt. 2007 Jan;78(1):31-8.

    ABSTRACT

    Results of preclinical and clinical studies implicate that, in addition to serotonin and norepinephrin, dopaminergic mechanisms play a role in the pathogenesis and treatment of depression. Newer antidepressants such as bupropion, sertraline, and venlafaxine act as partial inhibitors of presynaptic dopamine reuptake. Experimental studies show that dopaminergic effects contribute to the development of anxiety, depression, and anhedonia. These studies revealed, among the new nonergot dopamine agonists, anxiolytic properties for ropinirole and anxiolytic, antidepressive, and antianhedonic effects of pramipexole which seem to relate to its specific action on D(2) and D(3) receptors in the mesolimbic system and prefrontal cortex. In addition, affective disorders may be associated with impairments of neuronal plasticity, and pramipexole seems to exert neurotrophic properties. Controlled and open studies in depressed patients with Parkinson's disease show therapeutic effects of dopamine agonists on motor deficits, anhedonia, and depression. Various dopamine agonists have been tested in open studies in patients with depression and may add to the spectrum of treatment options in mood disorders. Recently published placebo-controlled trials in small patient groups implicate that pramipexole is effective as additional treatment to mood stabilizers in I and II bipolar depression.</div>

    I thought this was funny: they use the term antianhedonic. I'm guessing that awkward pretzel of a word is a result of the taboo nature of saying simply "hedonic".

    Ex Dubio, can you chime in on your dosage and time it took to develop tolerance to or recover from NE hypofunction?
    "Also, can I rig some sort of enema out of household items?" -Tussman

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    Senior Member Ex Dubio's Avatar
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    <div class='quotetop'>QUOTE (bdog527 @ Mar 24 2009, 09:02 AM) <{POST_SNAPBACK}></div><div class='quotemain'>I've been on it for oh...4 days now and so far no good for me. I'm tolerating it far better than I did bromocriptine it is essentially side effect free save for some pretty bad somnolence and strangely enough insomnia at the same time at only .25mgs a day. I've tried taking it at night and it sedates me but also speeds me up a little and makes it damn near impossible to sleep. When I take it in the morning I feel dopey and out of it and yawn all the time. Pretty damn strange overall and I guess I'm going to abandon my trial since I can't function at work on no sleep or feeling stoned. There are some pretty good anecdotal reports on the net about this stuff so I'm either a weird outlier, a pussy or both. [img]style_emoticons/<#EMO_DIR#>/huh.gif[/img]

    I remember reading loki's pergolide articles and I have no idea how he managed to tolerate that stuff.</div>

    Yeah, I've encountered much of the same issues. I'm still not entirely sure if it's an issue of adaptation (which may be as long as 2-4 weeks) or a long-term problem.

    It may be practical to titrate the dose as slowly as in 0.125mg increments. Somnolence is a common issue, though very easily offset with EC, dexedrine, pseudoepehedrine, or really any other sympathomimetic. The insomnia is an issue I encountered as well; try to avoid dosing it at night, because it'll fuck up your sleep pretty remarkably. I'd imagine it's terrible for sleep architecture as well.

    Though I don't have enough experience for me to feel confident about this, I would suggest:

    For sex, use infrequently at a dose of 0.25-0.5mg 1-2 hours before encounter. In my experience, this nicely reduced the refractory period to almost nothing, dramatically improved erectile strength, and shot libido through the roof. Very fun and pretty safe to use this way. If somnolence is an issue, combine with a mild stimulant.

    For depression/bipolar/other use, I would suggest titrating from 0.25mg 2x/day up in 0.25mg increments every 4-7 days (i.e. increase to 0.375mg 2x/day after a week) ; if especially sensitive to the side effects, starting at 0.125mg 2x/day and increasing weekly might be the best way to minimize them, though it will take a month to reach the studied 1mg/day dose.

    One more observation I should add. When I was bouncing around with different doses (inappropriate titration) early in my experiments, I would frequently experience feelings that I can only liken to mild opiate withdrawal in the evening. Stark dysphoria, tremors, excessive cold/hot sensitivity, sweating, shivering, muscle and joint pain, confusion, etc. Much of it resembled hypocortisolism/hypoglycemia as well, but I couldn't for the life of me correct it with glucose or hydrocortisone. I was combining it with a few other drugs that I take regularly (and have been for a while), so it's either an interaction or an artifact of poor dose titration. Either way, be aware of this, as the experience is quite unpleasant.

  18. #18
    Senior Member Ex Dubio's Avatar
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    <div class='quotetop'>QUOTE (FunkOdyssey @ Mar 24 2009, 10:51 AM) <{POST_SNAPBACK}></div><div class='quotemain'>I'm going to mess with this a little. I had some good times with cabergoline but I was scared off by heart valve concerns.

    What dose have you settled on Ex Dubio? How long did it take NE function to recover (as measured by fatigue, hypotension, etc) after initiating therapy?</div>

    Yeah, unfortunately pramipexole may share some heart valve concerns. This could really suck, though again, a few weeks playing with it certainly isn't going to hurt.

    If you go to RxList and click on Warnings and Precautions, you'll see that some postmarketing reports suggest a slightly increased rate of valve fibrosis. It was never established if that effect was due to D2 stimulation or due to some aspect of being an ergot-derivative. I wouldn't get too worried over this yet, as there may well not be causation (or patients may have been switched from an ergot-derivative), but it's something to keep in mind.

    That said, I'm quite sensitive to most drugs, so tend to employ a lower dose than most (e.g. I find 6.5mg/100mg EC or 10mg dextroamphetamine to be strongly stimulating), but I've greatly enjoyed 0.25mg used infrequently before sex. That use is more or less undoubtedly safe and, in my experience, very enjoyable and side-effect free.

    For other uses, I'm still playing with titration; as mentioned before, I think a 1mg/day total dose taken BID (twice per day) is probably good to shoot for, though I STRONGLY suggest titrating up to there. Also, and I forgot to mention this before, take the first dose early in the morning, and the second in early-to-mid-afternoon. Any later than that, and you get more dysphoria, somnolence, and sleep issues.

    If you guys try this stuff, I'd be very interested to hear your experiences.

    EDIT: Damnit, forgot to answer your second question. Expect a decent duration before it kicks in. For full disclosure, I take 10mg dextroamphetamine QD, so I'm not sure how that might affect things. For the first week or two, I threw in some EC early in the day (small amounts) to offset the sides in the morning. After that, they were tolerable, and after about 3 weeks essentially gone. That's a while, I know, but the results seemed worth it.

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    <div class='quotetop'>QUOTE (Jakeshorts @ Mar 24 2009, 11:34 AM) <{POST_SNAPBACK}></div><div class='quotemain'>Loki's article on pergolide is unreal. I think in one instance he passed out in them middle of campus. After taking bromo I can understand how it could happen.

    ftr - I think bromo's body composition effects were through D1 stimulation, and manifested itself via appetite suppression largely.

    As for this business, I'd say titrating on and off would be requisit. Be careful. If you already have high D levels and take a high dose of this stuff you could wake up in the middle of city hall naked as a jay bird.</div>

    Yeah, Loki, while a rather excellent wordsmith and a very smart man, is (or was) also a college student and not a very risk-averse one at that.

    Bromo's effects were never purported to be delivered through D1, though; a few articles in the book showed synergy with D1/D2 agonism, but bromocriptine is orders of magnitude (IIRC) stronger at D2 than at D1, and the effect on the latter is negligible. Cabergoline and pramipexole have mild D1 affinity, and of course pergolide had strong D1 affinity.

    No offense, but reducing this down to "high D levels" is incredibly reductionist. Even if we ignore the all-important question of "where?", you have to keep in mind that agonists, at least initially, reduce neurotransmitter release. Eventually, that effect is balanced by receptor downregulation and, according to the mouse study above, normalizes. Still, I don't believe it's understood where the rare inhibition-reducing effect of pramipexole comes from. I know I experienced nothing of the sort (very little in the way of anxiety or inhibition reduction).

    That said, D2 agonism has been associated with increases in OCD behavior when already present, so this may be a downstream aggravation of pre-existing compulsions.



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    I do have some Provigil laying around. Maybe that would help with the somnolence until my brain adjusted. [img]style_emoticons/<#EMO_DIR#>/dry.gif[/img]

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