Negative Effect of Antioxidants around Workouts

Madevilz

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Examine did an article some time ago on why you should avoid antioxidants around workouts, or high amounts of it in general, if hypertrophy is your main goal. https://examine.com/nutrition/antioxidants-muscle-building/

I generally avoid AO around preworkouts. Newer stuff like Vaso6, S7, Spectra and even Ashwaghanda have antioxidant properties.
Could they potentially be a problem if you want to optimize hypertrophy?
 

Resolve10

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This probably aligns closest with my thoughts.

So you probably won't find a direct answer.

It is also going to depend on the person and situation.

Considering some of these things (like Ash for example) have some studies showing increased lean mass I am going to say it probably isn't an issue, but it would be great for more research to help shed light.

Also check out Sweetlou's Post on Tumeric here. It kind of sheds light on the idea of how there are so many different things going on it can be hard to pinpoint or just leave it as antioxidant = bad and requires a lot more nuance.
 

SweetLou321

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Examine did an article some time ago on why you should avoid antioxidants around workouts, or high amounts of it in general, if hypertrophy is your main goal. https://examine.com/nutrition/antioxidants-muscle-building/

I generally avoid AO around preworkouts. Newer stuff like Vaso6, S7, Spectra and even Ashwaghanda have antioxidant properties.
Could they potentially be a problem if you want to optimize hypertrophy?
I agree with Resolve10's links and the information provided in them, I may be biased towards the second one though lol.

In general, I wouldn't worry about things that predominately function through the upregulation of Nrf2 as opposed to directly blunting the production of reaction oxygen species (ROS). Polyphenols from fruits, vegetables, Vaso6, S7, Spectra, ect will function more so by upregulating Nrf2. Vitamin C, E, NAC, ect will function more so by blunting ROS production directly. Here is some information I have written elsewhere for you to learn more:

Mitochondrial ROS

Mitochondrial ROS assists in the signaling cascade related to muscle repair following exercise-induced muscle damage (4). If an antioxidant is used to blunt mitochondrial ROS production after muscle damage has been acquired it can result in impaired recovery. Additionally, if an antioxidant is used during muscle damaging resistance exercise, it can result in a decline in force production with each contraction and lead to more damaged fibers after the session is completed. This is likely to due to the effect of ROS on mediating calcium ions in skeletal muscle. Calcium ion build-up can induce muscle damage. ROS, as oxidative stress, does have draw backs however, as its chronic elevations is also linked with decreased muscle growth, increased muscle damage, and decreased muscle function (2,5).

This means the process of mitochondrial ROS production is dynamic, its related positive effects on muscle tissue have a U-shaped curve, where too much can lead to increased muscle damage, diminished growth, and prolonged repair. This means that there is a need to maintain proper levels during and after exercise to achieve the benefits without the negatives.

Once exercise-induced muscle damage has occurred, ROS can induce the recruitment of infiltrating immune cells into muscle tissue (6). The ROS and inflammation caused by and produced by infiltrating immune cells can cause secondary muscle damage. This secondary damage phase can exacerbate existing muscle damage if not controlled appropriately. These immune cells do play a role in the adaptive process to resistance exercise, as muscle damage itself can lead to a resistance of muscle damage in the future, but likely not growth. Antioxidants are believed to decrease ROS that can signal these immune cells and thus this secondary cascade of damage. However, due to the drawback of antioxidants being able to blunt ROS during and after resistance exercise, there is a need for an alternative. Compound with antioxidant like activity are the most promise in helping maintain healthy ROS activity around exercise, specifically ones that upregulates nuclear factor erythroid 2 (Nrf2).

Nrf2 is a regulator of cellular resistance to oxidants (8). It mediates functions by a process called hormesis (7). Hormesis is the process in which a small amount of something damaging can lead to an upregulation of the defense systems needed to be prepared to handle that harmful stimulus better during the next exposure. Oxidative stress, specifically mitochondrial ROS, produced from muscle contractions leads to the upregulation of Nrf2 as a compensation mechanism (9). Increased Nrf2 activity then increases internal antioxidant production to help prevent future damage and repair current damage (3). As a result, increased Nrf2 activity mediates many of the oxidative stress-related adaptations to exercise (9). Upregulating Nrf2 would allow us to maintain ROS during and after exercise but mediate how much is released and present at baseline to prevent the negative effects of ROS.

Below are some pictures to help illustrate these concepts:

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  1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023708/
  2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893116/
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4556774/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5949579/
  5. https://www.hindawi.com/journals/omcl/2018/2063179/
  6. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0096464
  7. https://www.ncbi.nlm.nih.gov/pubmed/20122947
  8. https://www.ncbi.nlm.nih.gov/pubmed/20122947
  9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5078682/
  10. https://www.physiology.org/doi/full/10.1152/japplphysiol.01055.2014
 

SweetLou321

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Ill leave you with some more as well:

Cytokine Production

Increased Nrf2 activity and mitochondrial ROS are densely connected to the adaptive process of muscular cytokine production. ROS can damage muscle tissues and lead to the production of inflammatory cytokines from muscle fibers, activated satellite cells, and infiltrating immune cells. The increased antioxidant production due to increased Nrf2 activity can regulate exercise stimulated ROS related inflammation, but not abolish it, again hormesis (3). ROS can also enhance calcium function in the muscle cell leading to improved contractions and inflammation production by muscle fibers as a result (4). Outside of ROS stimulated inflammation, there are three other ways exercise can stimulate inflammation. The first is when a muscle contracts independent of ROS, it signals the production of cytokines in the muscle fibers (11). The second is when a muscle is damaged, infiltrating immune cells can generate an inflammatory response (11). The third is when satellite cells (precursor cells to muscle cells) that are activated by muscle stress produce inflammation (11). When a cytokine is produced in the muscle itself, they are termed as myokines, and these myokines have systemic benefits if they are released into circulation by impacting other tissues (11).

The main myokine we are going to focus on is interleukin 6 (IL-6). The release of IL-6 from muscle tissue from exercise can inhibit the production of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-a) in other tissues in the body, leading to an overall lower inflammatory status (8). This can benefit muscle growth as chronically elevated TNF-a can inhibit muscle cell differentiation, and its chronic elevation is associated with decreased muscle growth (9,10,17). IL-6 is proinflammatory in most cases but has this specific anti-inflammatory action when released from muscle tissue into circulation in an appropriate amount in an acute manner (8). Additionally, the release of IL-6 from muscle tissue from exercise in an acute manner can improve glucose and lipid metabolism (11). This is because IL-6 also functions as an energy sensor (11). If fuel substrate availability goes down during exercise, IL-6 is further produced by the contracting muscle and released into circulation to signal the release of stored substrates (11). As a result, the activity of enzymes, such as AMP-activated protein kinase (AMPK), are increased systemically. AMPK is a catabolic enzyme that signals the body to use energy instead of store it in the body. Its elevation can lead to improved glucose and lipid metabolism. AMPK also opposes mechanistic target of rapamycin (mTOR), which is an anabolic enzyme. Increased mTOR activity is linked with protein synthesis and muscle growth.

I am mentioning IL-6’s role as an energy sensor as research on nutrient timing has been shown to have some effects on IL-6 release around exercise that at first glance may be viewed as unfavorable based on what I have covered thus far. Carbohydrate and protein ingestion during exercise can blunt IL-6 release into circulation since energy availability is plentiful. However, this is unlikely to impact muscle growth as micro RNA (mRNA) expression of IL-6 in the muscle is maintained, and this means the muscle is still producing IL-6 in itself to signal adaptations. For the systemic benefits of IL-6 to occur, it must be released into circulation. Thus, intra-workout nutrition can blunt some of these effects.

Additionally, since contracting muscle can uptake IL-6 from circulation, the total IL-6 present in the muscle at the end of exercise can be lower. This may or may not be optimal as there is a threshold for IL-6 to be beneficial to muscle tissue as chronically elevated levels can lead to decreased growth, and acute bouts of extremely high levels can prevent muscle growth-related processes by causing damage to the muscle tissues and reduced mTOR activity. It has been seen that IL-6 in a proper amount in muscle tissue can promote mTOR activity and ribosome biogenesis as a result (41). Ribosome content is being identified as a key factor in determining how much volume we can do, how well we respond to that volume, and limiting factor in muscle growth (42, 43, 44). If the levels of IL-6 in the muscle exceed the level in which it promotes adaptations, then we can end up with diminished growth, loss of tissue, slower repair, or decreased ribosome biogenesis. Thus, intra-workout nutrition strategies are thought to be a great option to enhance recovery as it can help limit how much IL-6 ends up in the muscle tissue and can limit muscle damage as a result. While, intra-workout nutrition is not the focus of this series, the nuance of its effects on IL-6 production and release from muscle fibers will help us understand research we will discuss later.

Production of IL-6 from muscle fibers, infiltrating immune cells, and activated satellite cells can signal the release of other myokines that, alongside it, stimulate muscle growth and repair by initiating myogenesis, satellite cell recruitment, and tissue repair (11). Many researchers believe that IL-6 presence in the muscle or plasma after muscle growth-promoting exercise is not always linked with growth processes and can be present only to initiate repair processes. Research is starting to diverge that these processes may be separate, and tissue damage may not be a factor for muscle growth. Since muscle contractions can promote IL-6 production without muscle damage, we can see muscle growth-promoting factors are elevated at this time, and many growth signals can be present without damage (11). It is believed that IL-6 production by muscle fibers and activated satellite cells play a more significant role in muscle growth as they can respond to mechanical tension, a key driver of muscle growth. IL-6 from infiltrating immune is believed to play a more significant role in tissue repair as they respond to muscle damage. They also can cause further damage if not cleared away as they are generating inflammation and can lead to a chronic inflammatory state. This is not conclusive as further research is needed, but this is the current trend, and this concept will help us understand research we will discuss later.

Blunting the production of IL-6 and other key myokines by muscle fibers, infiltrating immune cells, and satellite cells can lead to decreased muscle growth and repair. Blunting the release of IL-6 from the muscle into circulation with antioxidants and anti-inflammatory compounds can reduce the anti-inflammatory, glucose metabolism, and lipid metabolism supporting effects of exercise. We want to maintain the release of myokines post-workout to enhance our health. For muscle growth, we want to maintain the production of IL-6 in the tissue. If antioxidants and anti-inflammatory compounds blunt the production of IL-6, then we can have diminished or blunted muscle growth and repair.

Signal Verse Noise Effect of Oxidative Stress and Inflammation

I think this is a good time to divert from some key mechanisms to talk about why the health community gives oxidative stress and inflammation such a bad reputation. Indeed, chronically elevated oxidative stress and inflammation levels are linked with most age-related diseases. These factors lead to the disruption and destruction of healthy tissues and, as a result, speeds up the aging process. The keywords in that last sentence are chronically elevated levels. The goal for those looking to maximize their health and response to exercise is to have healthy baseline levels of oxidative stress and inflammation and normal healthy peaks after exercise. There is a signal to noise effect of oxidative stress and inflammation when it comes to signaling adaptations after exercise. Since oxidative stress and inflammation post-exercise work as a signal to spark the adaptive process, if a higher baseline oxidative stress or inflammation status is present, then the signal from exercise can get lost in the noise that is the baseline status (18). If this is the case, then the body will not respond as well to the signals from exercise and adaptations will be decreased (18).
 

SweetLou321

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Muscle Damage

Now that we have reviewed some key adaptive processes and concepts related to oxidative stress and inflammation and the benefits of these factors, it is important to discuss some downsides in more depth. Exercise-induced oxidation and inflammation can also lead to muscle damage that creates the recovery time between workouts (12,13,14). This is especially true for isolated bouts or frequencies that are beyond the recovery capacity of the individual as there is a U-shaped curve with regards to the positive effects. The research is currently pointing towards muscle damage likely not being a causative factor for adaptations (this can be debated further and is outside of the scope of this series). If too much is present, then all of one’s resources can be spent trying to repair the damage, and little is left to stimulate the adaptations that lead to progress. It just so happens that what tends to be most effective for stimulating the signals for adaptations also increases muscle damage to a large extent. This trend in the research has caused debate on if antioxidants and anti-inflammatory compounds are useful to combine with exercise to reduce muscle damage, enhance recovery, and allow for better adaptations as a result.

While some view antioxidants and anti-inflammatory compounds as useful recovery tools, as some research has supported this notion, others argue that one is merely trading improved recovery for diminished adaptations (14). This is due to the data suggesting that various antioxidants and anti-inflammatory compounds can blunt the upregulation of Nrf2 produced from exercise, blunt the increase in mitochondrial ROS, blunt the release and production of IL-6, and blunt other transcription factors related to adaptations such as protein synthesis (2,3,15,16,19,20). When discussing recovery, we will be referring to the general idea of decreased muscle damage, improved return to performance, and reduced delayed onset

Antioxidant and Anti-Inflammatory Compounds in the Diet

After reviewing the potential pros and cons of antioxidants and anti-inflammatory compounds, that begs the question of how these compounds naturally occurring in our diet may impact our results. I personally do not think we should avoid these compounds as naturally occurring elements in our diet; in fact, I believe there is a strong basis that they provide many benefits to our exercise adaptations, body composition, and health. Animal research has shown that eating a diet full of these healthy components, such as omega-3 fatty acids, can benefit muscle growth and function (21). While animal data is not a one to one match for human data, it is an excellent research model to understand physiology in a very controlled setting. In this trial, the researchers generated a chronic inflammatory state and simulated resistance exercise in a placebo and anti-inflammatory diet group. The resistance exercise helped prevent muscle loss induced by the chronic inflammatory state, but the anti-inflammatory diet further prevented muscle loss. Similar effects have been seen in humans regarding a chronic inflammatory status and the use of compounds such as omega-3 fatty acids (23, 24).

When it comes to diet quality, it has been associated with the level of physical performance in humans (25). In marathon runners, the antioxidant vitamin A and a high naturally occurring intake in the diet was associated with lower pre-race IL-6 levels but was not associated with lower post-race IL-6 levels, which is what we want (22). Most of us think of antioxidant vitamins such as vitamin C when we talk about antioxidants, but a class of antioxidants we can acquire from a healthy diet in a large amount are polyphenols. Polyphenols are a class of non-essential compounds from plant foods; such are fruits and vegetables, which have antioxidant and anti-inflammatory properties. A high total dietary polyphenol intake is associated with a lower risk of substantial decline in physical performance in the elderly and may play a role in maintaining physical function throughout one’s lifespan (26). Dietary intake of polyphenols can be as high as one gram per day in various populations, and these amounts can match the quantities provided by supplements, but the intake from the diet does not seem to produce blood levels of those seen from supplemental preparations (27, 28). This may be due to how polyphenols in the diet typically have a lower bioavailability than supplemental preparations (22). As a result of this difference, dietary polyphenols can undergo biotransformation by the bacteria in our gut microbiome, and the metabolites can then be absorbed (30). These altered compounds can provide their antioxidant and anti-inflammatory effects by upregulating Nrf2 instead of fighting ROS production directly (29). Another potential mechanism of benefit is that the gut microbiome shift that can result as of polyphenol exposure may impact our oxidant and inflammatory status (30). Some very early research even suggests that the status of our gut microbiome may directly impact exercise performance and muscle growth (31, 32).

Polyphenols such as anthocyanins, flavan-3-ols, and proanthocyanidins (that can be found in oranges, grapes, and berries as examples) are associated with lower fat mass independent of shared genetics or other dietary components in female twins ages 18-83 (33). When humans are given 200 grams of frozen blueberries in a smoothie around eccentric exercise, it does not impact post-workout inflammatory markers such as IL-6 up to 60 hours after (34). Oxidative stress at the 36-hour mark does start to be attenuated but by naturally occurring antioxidant production, which is characteristic of upregulated Nrf2 (34). They also noted faster recovery of some return to performance markers during the 60-hour post-workout window compared to the placebo (34). The polyphenols naturally occurring in coffee are associated with additional endurance and resistance training performance on top of what caffeine alone provides (35). In young men who resistance train and whose diet lacks an abundance of overall antioxidant compounds, when three cups of green tea are added to get their antioxidant intake to a level typically seen with a healthy diet, they have less muscle damage after resistance training, an increase in internal antioxidant activity, and no meaningful effect on oxidative stress markers 15 minutes post-workout (36). Two weeks of 40 grams of dark chocolate consumption reduced the oxygen cost of moderate-intensity exercise and improved performance (37). Lastly, since we should be focused on exercise adaptations and health together, a high dietary polyphenol intake is linked with overall longevity (40).

Other dietary components worth mentioning are choline and betaine. Choline is an essential nutrient found in high amounts in foods such as eggs and meat. It has antioxidant and anti-inflammatory proprieties (38, 39). Betaine is an active metabolite of choline and can be found in grains, fruits, vegetables, meat, and dairy. It also has both antioxidant and anti-inflammatory proprieties (45, 46). In a study investigating if there is an association with better body composition in an adult population, they found that those with the highest intakes of dietary choline and betaine had the least amount of body fat and the most muscle mass (47).

Given the data presented in both animal and human models, I feel a healthy diet providing antioxidant vitamins, a wide variety of polyphenols, omega-3 fatty acids, choline, and betaine is supportive of exercise performance, exercise adaptations, body composition, and overall health. I do not see a reason to avoid these health-promoting compounds in the diet or around exercise as a result.
 

SweetLou321

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Supplementation and Use of Medications with Antioxidant and Anti-Inflammatory Effects

The main area of debate regarding the pros and cons of these compounds in the conjunction with exercise and health is whether supplementation and the use of medications with antioxidant and anti-inflammatory effects is beneficial or harmful. A recent meta-analysis has helped to provide some clarity to this issue of supplemental antioxidant vitamins on exercise outcomes (48). The meta-analysis looked at clinical end-points of the effects of the non-specific antioxidant compounds (those that seem to affect the whole body) vitamin C and E on exercise adaptations, and they did not demonstrate inhibition of any resistance or aerobic training related exercise-induced adaptations in the selected trials (48). One of the limitations of this body of literature is in the length of the trials. Some antioxidants such as vitamin E have a slow incorporation into the lipid bilayer, and it varies from tissue to tissue. (49). If more time is provided in a trial it is suspected that the potential negative effects of the use of these compounds in high dosages will become more detectable. In trials of 10-12 weeks of length vitamin C and E supplementation has been shown to inhibit the release of IL-6 from exercised muscle tissue but not mRNA IL-6, altered beneficial protein signaling but not muscle growth in younger subjects, and showed the ability to blunt some muscle growth in elderly men (50, 51, 52). What is really interesting is that the elderly men showed potential blunting of muscle growth from the use of these compounds as they are more likely to have higher baseline oxidative stress due to the aging process. In a four-week trial, the use of these compounds inhibited many of the health promoting effects of exercise that are caused by the upregulation of Nrf2, mitochondrial ROS production, and cytokine production (53). These compounds can inhibit mitochondrial ROS production directly and remove any need for the body to upregulate Nrf2 as a result of exercise. If longer trials were carried out it is possible that these compounds could inhibit mRNA IL-6 and really affect the muscle growth process and the exercise performance effects of exercise. Additionally, research is highly mixed if these compounds can improve recovery status, which is the main reason one would supplement these items in relation to exercise (54, 55). Another none specific antioxidant, N-acetyl-cysteine (NAC) has actually been shown to reduce DOMS in the short term (days 1-4) and increase DOMS in the long term (days 5-6) (56). I would suggest being cautious using high supplemental dosages of nonspecific antioxidants long term (beyond 10-12 weeks) when it comes to the adaptations to exercise. I would suggest keeping supplemental vitamin C dosages below 500 milligrams, keeping supplemental vitamin E dosages below 400 IU of alpha-tocopherol, and suggest keeping supplemental NAC dosages below 1,000 milligrams as examples. Nonspecific antioxidants such as vitamin C, vitamin E, and NAC and their effects both in the real world and their mechanisms gives a research base to asses other possible options for use.

While the use of supplemental nonspecific antioxidants appears to be compatible with exercise in the short term with some doubt regarding long-term use (with little upside of use), let us now look at human trials using anti-inflammatory molecules. Research shows the use of nonsteroidal anti-inflammatory drugs (NSAIDs) can blunt adaptations in young healthy people with healthy baseline inflammation levels but enhance exercise adaptations in healthy older adults due to their higher inflammation status (57, 58). This contrast is due to the signal verses noise effect of inflammation on adaptations we discussed earlier. Many younger athletes with healthy baseline inflammation levels still look to NSAIDs to help with DOMS and to speed up recovery from exercise despite this research. NSAIDs are thought to possibly help with exercise-induced muscle damage (EIMD) by inhibiting the COX and LOX enzymes. COX-1 is one of the main active inflammatory enzymes in muscle tissue. It is the main COX enzyme that regulates post exercise protein synthesis and prostaglandin production that promotes and works alongside to IL-6 help mediate inflammatory based adaptations (59, 60). COX-2 inhibition is linked with decreased muscle growth and repair processes (63). This enzyme is also linked with the production of M2 macrophages that play a large role in clearing infiltrating immune cells and signaling tissue repair (63). The COX and LOX enzymes play a large role in the switch from the production of proinflammatory lipid mediators from omega fatty acids into inflammation resolving mediators from these compounds (64). These inflammation resolving compounds are call specialized pro-resolving mediators (SPMs) and they help with clearing infiltrating immune cells, promote inflammation resolution, and tissue repair (64). In fact, NSAID use around a resistance training workout can blunt both the production of proinflammatory lipid mediators and SPMs (65). This is partially due to COX and LOX being inhibited but also inflammation is a trigger for SPM production. SPMs have some mechanisms by which they can directly support muscle growth alongside their role in supporting repair (67). NSAID use has also been shown to inhibit IL-6 levels in the blood after exercise and this marker is used as proxy to speculate that intramuscular production is inhibited as well (66). Given the conflicting mechanisms on inhibiting muscle damaging promoting inflammation and repair supporting SPMs, the research is mixed if they can reliably provide a benefit to recovery (61). I would caution the use of things that can possibly negatively impact adaptations, which NSAIDs can (62). NSAIDs and their effects both in the real world and their mechanisms provide a research base we can use to asses other possible options for use. Since these anti-inflammatory compounds can blunt adaptations and not even provide reliable benefits to recovery in young people with healthy baseline levels of inflammation, this creates the need for options that can regulate inflammation based muscle damage, enhance recovery, and reduce joint pain that is commonly experienced by seasoned athletes who are still young and likely have healthy baseline levels of inflammation in general.

The last compound we are going to discuss to use as a research base is the use of the drug Metformin with exercise. Metformin is a type-2 diabetic medication that provides its effects primarily by upregulating AMPK. It also has the ability to inhibit ROS of the mitochondria. It was through to be a good option to combine with exercise since it can increase glucose metabolism (linked with decreased results from exercise if poor) and increase M2 macrophage amounts in muscle tissue (linked with how well we respond to resistance training). In a trial looking at the combination of Metformin with aerobic exercise it blunted ROS based adaptations and worsened glucose control (68). In a trial looking at the combination of Metformin with resistance training it blunted muscle growth by stimulating baseline AMPK and thus having an inhibiting effect on mTOR chronically (69). Even though the mechanisms without exercise appeared promising this compound is not likely to a good candidate to promote adaptations. Compounds that inhibit mitochondrial ROS and mTOR are likely to not be good options to combine with exercise. This compound and its real-world effects and its mechanisms will help you assess if other similar compounds are to be used or not.
 

SweetLou321

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  67. https://pdfs.semanticscholar.org/8b93/3b681d2f8ea53b255d290f13c4b442784648.pdf
  68. https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12880
  69. https://onlinelibrary.wiley.com/doi/full/10.1111/acel.13039
 

SweetLou321

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I left some stuff out, but this should give enough background one to understand many of nuances of this topic. If anyone has questions, I am happy to help further.
 

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