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  1. #1
    Senior Member Ex Dubio's Avatar
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    I feel as if this topic must have arisen on this board before, but I could not -- with a cursory glance -- find a mention of it. Fish oil seems to be something of a "no-brainer" supplement, with benefits on virtually every health-related parameter imaginable. And indeed, many on this board take considerable doses of fish oil regularly. However, many on this board also suffer from HPA-related maladies, particularly those characterized by a hypoactive stress response.

    Though I'd not have hypothesized a relationship between fish oil (EPA/DHA) supplementation and the HPA, it seems a substantial one exists. I can't say I've performed a comprehensive review of the literature, but here's what's turned up. Note that the first two studies are very new; they were published online just a week ago.

    (PMID: 20466437) This study compared patients with major depression treated with either 1g EPA/day, 20mg fluoxetine/day, or a combination of the two treatments. The findings showed that all three treatments tended to decrease HPA activity and, in particular, plasma cortisol. This may seem unsurprising, given that major depression of the melancholic type is associated with a hyperactive HPA, but the authors found that cortisol suppression was not correlated with symptom improvement. In other words, the drugs -- not the resolution of symptoms -- led to HPA suppression. And indeed, the authors noted that EPA itself may show efficacy in depression specifically by reducing HPA activity. It should be noted that the authors found that EPA was as effective as fluoxetine in symptomatic improvement.

    (PMID: 20303394) This study compared the effects of exercise and DHA intake in [healthy] rats. They looked at leptin, ghrelin, AMPK, and SIRT1 in addition to HPA-related parameters, but I will not mention these findings. The authors found:

    -In the hypothalamus, exercise increased GR expression whereas DHA reduced GR expression. Exercise and DHA together had no effect.
    -In the hippocampus, GR expression was increased by DHA, exercise, and their combination.
    -In the hypothalamus, 11betaHSD1 was increased only by DHA, with no changes in the other groups.
    -In the hippocampus, 11betaHSD1 was increased by DHA, exercise, and their combination.

    To oversimplify GR dynamics extensively, GR binding in the hypothalamus reduces HPA output, whereas GR binding in the hippocampus increases HPA output. Moreover, 11betaHSD1 (which converts corticosterone to cortisol, and thus has a positive effect on local cortisol concentrations) in the hypothalamus tends to reduce HPA output by increasing negative feedback, whereas 11betaHSD1 in the hippocampus tends to increase HPA output by increasing GR binding. In short, DHA has unclear effects in the hypothalamus (decreased GR but increased 11betaHSD-1) but positive effects on the hippocampus (increased GR and increased 11betaHSD1).

    (PMID: 17055120) Healthy men were administered LPS, a commonly employed endotoxin. LPS alone caused massive HPA activation, leading to fever, increased ACTH, increased plasma cortisol, and cytokine release. Fish oil (17% EPA, 11% DHA) administration for 3-4 weeks beforehand blunted fever as well as ACTH and cortisol plasma levels, but had no effect on cytokine release.

    (PMID: 12909818) "Seven human volunteers were studied on two occasions, before and after 3 weeks of supplementation with 7.2 g/day fish oil." (Fish oil was 17% EPA, 11% DHA). "After 3 weeks of a diet supplemented with n-3 fatty acids, the stimulation by mental stress of plasma epinephrine, cortisol, energy expenditure, and plasma non esterified fatty acids concentrations, were all significantly blunted." This effect is presumably mediated by the CNS.

    (PMID: 11237197) In study 1, 41 college students took either a DHA capsule (1.5g DHA) or a control capsule daily for 3 months. The study ended in the middle of the mental stress of final exams. In the control group, hostility had increased significantly compared to the start of the study, whereas in the DHA group no change was found.

    In study 2, plasma catecholamines and cortisol were measured for 7 students from the previous study. The authors note: "In study 2 the students were under a continuous stress of final exams that lasted for two mon throughout the whole study period. The plasma cortisol did not change in either group, but the norepinephrine concentration was significantly decreased in the DHA group (-31%), whereas it stayed at the same level in the control group."

    Summary

    It's seemingly undeniable that fish oil has numerous health benefits, but the HPA-related effects of EPA and DHA are neither positive (in conditions of hypoactive HPA activity) nor equal. Based on the above, admittedly limited, evidence, it would seem that EPA has a direct effect reducing HPA activity in response to stress. Its effects on baseline HPA activity are unclear. On the other hand, DHA seems to have conflicting molecular effects on the HPA, and the only study examining its cortisol- and catecholamine-related effects found no change in cortisol and a decrease in NE vs. control during a period of mental stress. It does seem, however, that fish oil containing 17% EPA and 11% DHA does reduce HPA activity in response to both mental and immunological stress.

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    this has indeed been discussed before, I remember having posted about my fish oil experience several times, but I think it was never discussed in a thread of his own.

    so, anecdotally, I am just crawling out of a dark hole, I maneuvered myself into by nothing else than a 5g dose of fish oil a day. I had some joint issues and (stupid me) got back on the fish oil track without remembering that
    1. it does make me tired and sluggish
    2. it does make me appear flat (muscles)
    3. it does make me retain water and look bloated (mid section)

    if you have a look at my thread about passing the fish oil and grabbing the lard, you will notice, that the effects of n-3 fatty acids on (male) endocrine balance are overall negative, and I assume that is what I am currently experiencing
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  3. #3
    Senior Member FunkOdyssey's Avatar
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    <div class='quotetop'>QUOTE (Ex Dubio)</div><div class='quotemain'>I feel as if this topic must have arisen on this board before, but I could not -- with a cursory glance -- find a mention of it. Fish oil seems to be something of a "no-brainer" supplement, with benefits on virtually every health-related parameter imaginable.</div>

    The epidemiologically observed health benefits of fish oil intake max out fairly low, we're talking like 500-700mg of combined DHA + EPA IIRC. Not to mention the fact that when you eat actual fish, a majority of the omega 3 is typically DHA, not the high EPA ratio of commercial fish oil.

    So I wouldn't call typical fish oil supplementation a no-brainer as far as health benefits go, more like a huge EPA overdosing experiment that thousands are participating in.
    "Also, can I rig some sort of enema out of household items?" -Tussman

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    So fish oil blunts stress response. I knew that already. But is it really a problem? Lots of stuff blunts stress response. Like Rhodiola, Vitamin C, Phosphatidylserine. But don't we want this? I mean, at least we want excessive stress response to be blunted. Lots of us with stress related problems seem to have an excessive reaction to stress. And since extra stress further exarcebates the problem, why wouldn't we want to take something that increases our stress tolerance? Does fish oil also lower baseline cortisol?

    Fish oils also lower inflammation. And inflammation is a big problem in these syndromes. And since inflammation contributes negatively to HPA hypofunction (and depression), that should be a good thing. So again, I'm surprised if this is a negative thing.

    But maybe someone can explain to me the difference between increased stress tolerance, and a blunted stress response?

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    <div class='quotetop'>QUOTE (FunkOdyssey @ Jun 7 2010, 07:11 AM) <{POST_SNAPBACK}></div><div class='quotemain'>The epidemiologically observed health benefits of fish oil intake max out fairly low, we're talking like 500-700mg of combined DHA + EPA IIRC. Not to mention the fact that when you eat actual fish, a majority of the omega 3 is typically DHA, not the high EPA ratio of commercial fish oil.

    So I wouldn't call typical fish oil supplementation a no-brainer as far as health benefits go, more like a huge EPA overdosing experiment that thousands are participating in.</div>

    I was under the impression that the natural EPA/DHA ratio is 1.5.

  6. #6
    Senior Member FunkOdyssey's Avatar
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    <div class='quotetop'>QUOTE (adrenoguy @ Jun 7 2010, 03:45 AM) <{POST_SNAPBACK}></div><div class='quotemain'>I was under the impression that the natural EPA/DHA ratio is 1.5.</div>

    No, actually its probably opposite of that.

    DHA and EPA content of common seafood

    This isn't exactly scientific but I pasted that table into excel and here are the averaged results for DHA and EPA:

    DHA per 100g: 0.481g
    EPA per 100g: 0.328g

    See what I'm saying now?
    "Also, can I rig some sort of enema out of household items?" -Tussman

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  7. #7
    Senior Member KimberCT's Avatar
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    <div class='quotetop'>QUOTE (Ex Dubio @ Jun 6 2010, 11:02 PM) <{POST_SNAPBACK}></div><div class='quotemain'>Based on the above, admittedly limited, evidence, it would seem that EPA has a direct effect reducing HPA activity in response to stress. Its effects on baseline HPA activity are unclear. On the other hand, DHA seems to have conflicting molecular effects on the HPA, and the only study examining its cortisol- and catecholamine-related effects found no change in cortisol and a decrease in NE vs. control during a period of mental stress.</div>

    I'm glad you posted this. It may explain why I do better when I don't supplement fish oil. I was guilty of high consumption of high EPA ratio fish oil softgels for years.

    Now I'm considering products like Jarrow Max DHA (35mg EPA : 250mg DHA) for the norepinephrine reduction while maintaining cortisol levels.

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    Senior Member FunkOdyssey's Avatar
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    "Also, can I rig some sort of enema out of household items?" -Tussman

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    Senior Member Kimbo's Avatar
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    <div class='quotetop'>QUOTE (FunkOdyssey @ Jun 7 2010, 09:44 AM) <{POST_SNAPBACK}></div><div class='quotemain'>No, actually its probably opposite of that.

    DHA and EPA content of common seafood

    This isn't exactly scientific but I pasted that table into excel and here are the averaged results for DHA and EPA:

    DHA per 100g: 0.481g
    EPA per 100g: 0.328g

    See what I'm saying now?</div>
    I recall you mentioning this a while back, and I recently switched over to Carlson's cod liver oil, which seems to have a more favoriable EPAHA ratio (a bit more DHA than EPA, I can't remember the numbers off the top of my head). 1tbsp total of oil daily for now, as I am a Fatty McFatster.

    I'll be sure to point out anything I notice. The only thing I've noticed so far is that I'm bleeding like a mofo when I cut myself, moreso than I think I was before when I used other stuff (no idea why this would be though).


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    Senior Member lordshockspeare's Avatar
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    <div class='quotetop'>QUOTE (Kimbo @ Jun 7 2010, 08:20 AM) <{POST_SNAPBACK}></div><div class='quotemain'>I recall you mentioning this a while back, and I recently switched over to Carlson's cod liver oil, which seems to have a more favoriable EPAHA ratio (a bit more DHA than EPA, I can't remember the numbers off the top of my head). 1tbsp total of oil daily for now, as I am a Fatty McFatster.

    I'll be sure to point out anything I notice. The only thing I've noticed so far is that I'm bleeding like a mofo when I cut myself, moreso than I think I was before when I used other stuff (no idea why this would be though).</div>

    I believe fish oil reduces your bodies blood clotting ability, which I think is one of its cardio-vascular benifits for the stuff. I personally notice this in the form of nose bleeds. If I am taking fish oil then I get nose bleeds all the time. This thread goes to show the a balanced whole food diet is probably the best way to go.
    We see things not at they are, but as we are

  11. #11
    Senior Member Ex Dubio's Avatar
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    <div class='quotetop'>QUOTE (adrenoguy @ Jun 6 2010, 10:16 PM) <{POST_SNAPBACK}></div><div class='quotemain'>So fish oil blunts stress response. I knew that already. But is it really a problem? Lots of stuff blunts stress response. Like Rhodiola, Vitamin C, Phosphatidylserine. But don't we want this? I mean, at least we want excessive stress response to be blunted. Lots of us with stress related problems seem to have an excessive reaction to stress. And since extra stress further exarcebates the problem, why wouldn't we want to take something that increases our stress tolerance? Does fish oil also lower baseline cortisol?

    Fish oils also lower inflammation. And inflammation is a big problem in these syndromes. And since inflammation contributes negatively to HPA hypofunction (and depression), that should be a good thing. So again, I'm surprised if this is a negative thing.

    But maybe someone can explain to me the difference between increased stress tolerance, and a blunted stress response?</div>

    There are two questions here, one of the long-term needs and the other of short-term.

    First, it's important to make clear what we mean by an excessive reaction to stress. Many posters on this forum complain of stress-related symptoms that largely revolve around stress-induced anxiety and fatigue. But these symptoms are not due to an excessive cortisol response to stress; rather, they are due to an insufficient cortisol response to stress. The key here is recalling that cortisol largely blunts the sensation of stress. Feeling "stressed", excessively and chronically, under relatively low-stress conditions, suggests an inappropriately habituated (low) cortisol response to stress.

    Thus, the acute problem in syndromes of inappropriately low HPA activity is that HPA (read: cortisol) output is not sufficient to counteract stress-induced immune and sympathetic activation. As a result, flu-like symptoms result.

    Chronically, of course, the problem may be overactivity of one of several of: the immune system, the SNS, CNS acetylcholine, hypothalamic NE, hippocampal 5-HT, or something else entirely. And indeed, this conditions seem brought on when an extended stressor is finally removed.

    If we are looking at short-term, palliative treatment, then fish oil is obviously deleterious, as it will only exacerbate the condition of low HPA activity. The picture for long-term, permanent HPA restoration is murkier. The problem is that HPA negative feedback hypersensitivity is controlled by a number of factors (endocannabinoids, 5-HT, and NE to name a few), and the "root" problem -- if there can be said to be one -- likely does not relate to actual ACTH or cortisol levels, but rather to an interplay between CRH and other hypothalamic factors.

    The upshot is that "curing" atypical depression, "adrenal fatigue", or whatever hypoactive HPA syndrome is in question will be a matter of moderating the neurological factor inducing HPA hypersensitivity. If fish oil is modulating this factor (and thus, presumably, leading to a long-term reduction in feedback hypersensitivity), then it will have a positive effect. On the other hand, if fish oil is simply, say, blocking ACTH release, then it will not fix the root cause and instead merely worsen symptoms.

    This is a difficult point to articulate precisely, but the point is that simply reducing the stress response by a downstream mechanism only exacerbates the problem. Reducing the stress response at an upstream target (SSRIs do this, for example), however, should have more profitable effects.

  12. #12
    Senior Member Kimbo's Avatar
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    <div class='quotetop'>QUOTE (lordshockspeare @ Jun 7 2010, 12:41 PM) <{POST_SNAPBACK}></div><div class='quotemain'>I believe fish oil reduces your bodies blood clotting ability, which I think is one of its cardio-vascular benifits for the stuff. I personally notice this in the form of nose bleeds. If I am taking fish oil then I get nose bleeds all the time. This thread goes to show the a balanced whole food diet is probably the best way to go.</div>
    Yes, I know that. What I said was that the bleeding seems to be much more pronounced compared to other fish oils (EPA<DHA) I've used. I can't say whether it's because of the ratio or something else, though.

    But, I would agree that the best thing to do is to get in a decent diet (e.g. wild salmon, grass fed beef, lots of veggies, etc.)


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    <div class='quotetop'>QUOTE (Kimbo @ Jun 7 2010, 10:20 AM) <{POST_SNAPBACK}></div><div class='quotemain'>I recall you mentioning this a while back, and I recently switched over to Carlson's cod liver oil, which seems to have a more favoriable EPAHA ratio (a bit more DHA than EPA, I can't remember the numbers off the top of my head). 1tbsp total of oil daily for now, as I am a Fatty McFatster.

    I'll be sure to point out anything I notice. The only thing I've noticed so far is that I'm bleeding like a mofo when I cut myself, moreso than I think I was before when I used other stuff (no idea why this would be though).</div>

    Carlson's cod liver oil is DHA-500mg, EPA-400mg, ALA-40mg.


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    instead of suggesting specific supplement brands, I would like to return to the topic, by posting the following study, which - although it aint on EPA - is closely related as ALA > EPA
    <div class='quotetop'>QUOTE </div><div class='quotemain'>Nan Fang Yi Ke Da Xue Xue Bao. 2010 Apr;30(4):664-7.
    [Effects of alpha lipoic acid on hypothalamus-pituitary-adrenal axis in rats.]

    [Article in Chinese]

    Bu L, Liu ZM.

    Department of Endocrinology, Changzheng Hospital, Shanghai 200003, China. E-mail: geyingjun@hotmail.com.
    Abstract

    OBJECTIVE: To study the functional and ultramicrostructural effects of alpha lipoic acid on hypothalamus-pituitary-adrenal (HPA) axis in normal and diabetic rats. METHODS: Using radioimmunoassay we observed the effects of three doses (1, 20, and 100 mg/kg) of alpha lipoic acid injected intraperitoneally for 3 weeks on the plasma levels of CRH, ACTH and COR in normal and diabetic rats. The ultramicrostructural changes of the hypophysis and pituitary gland after alpha lipoic acid treatment were observed under transmission electron microscope. RESULTS: Compared with the control group, CRH level in lipoicin-treated normal and diabetic rats was significantly reduced (P<0.05). ACTH level of the 3 lipoicin doses groups of normal rats decreased, and a significant reduction occurred in medium-dose lipoicin group of diabetic rats (P<0.05). COR level showed the same changes as CRH level in normal rats, but decreased significantly in high- and medium-dose lipoicin groups of diabetic rats. Lipoicin treatment produced no apparent effect on the ultramicrostructures of the hypophysis and pituitary gland cells, which were the targets of diabetic lesions with low metabolism functions. Lipoicin treatment obviously enhanced the hypophysis and pituitary gland cell metabolism function to resist diabetic oxidative stress. CONCLUSION: Lipoicin can inhibit the HPA axis directly or indirectly in normal and diabetic rats.

    PMID: 20423821 [PubMed - in process]Free Article</div>
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    <div class='quotetop'>QUOTE (Physicus007 @ Jun 8 2010, 12:34 PM) <{POST_SNAPBACK}></div><div class='quotemain'>instead of suggesting specific supplement brands, I would like to return to the topic, by posting the following study, which - although it aint on EPA - is closely related as ALA > EPA</div>

    That is surely interesting, and explains why I feel worse taking it, but aren't you confusing Alpha-Lipoic Acid with Alpha-Linolenic Acid?

  16. #16
    Senior Member FunkOdyssey's Avatar
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    He is confusing the two but that's actually a very important study to have posted so kudos for that.
    "Also, can I rig some sort of enema out of household items?" -Tussman

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    Senior Member FunkOdyssey's Avatar
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    Watch out for ginger as well?

    <div class='quotetop'>QUOTE </div><div class='quotemain'>Biol Pharm Bull. 2004 Oct;27(10):1679-82.
    Comparison of the effects of Sho-hange-ka-bukuryo-to and Nichin-to on human plasma adrenocorticotropic hormone and cortisol levels with continual stress exposure.

    Katagiri F, Inoue S, Sato Y, Itoh H, Takeyama M.

    Department of Clinical Pharmacy, Oita University Hospital, Hasama-machi, Japan. FKATA@med.oita-u.ac.jp
    Abstract

    Sho-hange-ka-bukuryo-to and Nichin-to, traditional Chinese herbal (Kampo) medicines have been used to treat vomiting and nausea. Traditional herbal medicines have frequently been used in the empirical treatment. Some patients who take these medicines have no organic disease but have conditions classified as non-ulcer dyspepsia (NUD). To determine the pharmacological effects of Sho-hange-ka-bukuryo-to, Nichin-to, and the two herbs (Pinelliae Tuber and Zingiberis Rhizoma, both of which are included in Sho-hange-ka-bukuryo-to and Nichin-to), we examined the effects of these medicines on the plasma levels of adrencorticotropic hormone (ACTH) and cortisol under stress conditions by repetitive blood sampling. After a single administration of Kampo medicine or a placebo, venous blood samples were taken before and 20-240 min after administration. A single administration of Sho-hange-ka-bukuryo-to caused significant suppression of an increase in plasma ACTH-immunoreactive substance (IS) levels at 120 to 180 min and tended to suppress increases in plasma cortisol levels at 240 min, compared with the response to a placebo. A single administration of Nichin-to caused significant suppression of increases in plasma ACTH-IS levels at 120 min compared with a placebo group, but had no effect on plasma cortisol levels. Pinelliae Tuber had no significant effects in plasma ACTH-IS or cortisol, but Zingiberis Rhizoma significantly suppressed the increase of ACTH-IS (120 min) and cortisol (180 min). These medicines have a modulatory effect on the hypothalamo-pituitary-adrenal (HPA) axis and autonomic nervous function. These effects might be beneficial in stress-related disease and suggest that this medicine has clinical pharmacological activity.

    PMID: 15467219</div>
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    Uh-oh. This is turning into the "everything bad for the HPA axis" thread.

    ALCAR is next:

    <div class='quotetop'>QUOTE </div><div class='quotemain'>Exp Gerontol. 1994 Sep-Oct;29(5):569-74.
    Effect of long-term acetyl-L-carnitine on stress-induced analgesia in the aging rat.

    Ghirardi O, Caprioli A, Ramacci MT, Angelucci L.

    Institute for Research on Senescence, Sigma Tau S.p.A., Pomezia, Italy.
    Abstract

    Cold water swim (CWS) analgesia in the rat is mediated by the hypothalamo-pituitary-adrenocortical (HPA) axis. An age-dependent increase of CWS-induced analgesia was observed in male Sprague-Dawley young (4 months), adult (15 months) and old (26 months) rats. Acetyl-L-Carnitine (ALCAR) chronically administered (75 mg/kg/daily in drinking water for 8 months) to old rats was able to maintain the stress-dependent response at the same levels as in adult rats. This effect may be explained by ALCAR capability of retarding the age-dependent loss of glucocorticoid receptors in the hippocampus, thus maintaining the glucocorticoid competence of this structure which exerts a negative feedback control over the HPA axis activity.

    PMID: 7828664 [PubMed - indexed for MEDLINE]</div>

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    Senior Member FunkOdyssey's Avatar
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    I don't know about that one, preventing an age-related loss is not the same as increasing GR density. And again, real world results = ALCAR definitely helps chronic fatigue (in addition to some 20 studies in pubmed to this effect).
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    <div class='quotetop'>QUOTE (FunkOdyssey @ Jun 8 2010, 06:21 PM) <{POST_SNAPBACK}></div><div class='quotemain'>I don't know about that one, preventing an age-related loss is not the same as increasing GR density. And again, real world results = ALCAR definitely helps chronic fatigue (in addition to some 20 studies in pubmed to this effect).</div>

    Ok, I'll accept that.

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