From NADPARK to NOPARK

# # # # Researchers in Norway recently published the results of a small pilot study investigating the therapeutic potential of a form of Vitamin B3 – called nicotinamide riboside – in people with Parkinson’s. The results of that randomised, double-blind study were encouraging as they demonstrated that orally-administered nicotinamide riboside treatment could boost energy levels in the brain and reduce the amount of inflammatory signaling. The study was small, but provides strong justification for a much larger, ongoing Phase II clinical trial evaluating the disease modifying potential of nicotinamide riboside in 400 people with Parkinson’s. In today’s post, we will discuss what nicotinamide riboside is, review the results of the published study, and explore what the ongoing trial looks like. # # # #

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Tromso, Norway (best new year’s eve ever!). Source: Outdooractive

As you read, you may notice that there is a slight Norwegian theme running through today’s post.

And it begins with Conrad Elvehjem:

Conrad Elvehjem. Source: Aboutnad

Who was Conrad Elvehjem?

He was the son of Norwegian emigrants to the US, and in 1937, he published this report:

Title: The isolation and identification of the anti-black tongue factor. 1937 (reprinted).
Authors: Elvehjem CA, Madden RJ, Strong FM, Wolley DW.
Journal: J Biol Chem. 2002 Aug 23;277(34):e22.
PMID: 12243127              (This report is OPEN ACCESS if you would like to read it)

In this study, Elvehem and colleagues noted that when dogs get pellagra (a vitamin B₃ deficiency disease) due to a poor diet, their tongues would turn black. This curious feature provided the researchers with an assay to test different food extracts on the dogs and see which ones could rescue the animals from the “black tongue disease”.

Their efforts led to the discovery of two vitamins – Nicotinic acid (also known as niacin) and nicotinamide – which cured the “black tongue disease” in the dogs. They are both forms of “vitamin B₃” and they are now recognised as precursors of nicotinamide adenine dinucleotide (or NAD+).

What is –

We’ll come to that in a minute. Just let me get the intro out of the way.

The discovery of two forms of vitamin B₃ was remarkable. But it was what happened 67 years later that was even more remarkable, and it was announced in this study:

Title: Discoveries of nicotinamide riboside as a nutrient and conserved NRK genes establish a Preiss-Handler independent route to NAD+ in fungi and humans.
Authors: Bieganowski P, Brenner C.
Journal: Cell. 2004 May 14;117(4):495-502.
PMID: 15137942            (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers announced the discovery of a third form of vitamin B₃ and another precursor to NAD+.

That new precursor was nicotinamide riboside.

Ok, stop. What is nicotinamide riboside? And what is NAD+ and nicotinamide ade…nine dinuc…stuff?

Nicotinamide adenine dinucleotide (or NAD) is a biomolecule that plays a pretty critical role in a wide range of cellular biochemistry.

NAD. Source: Wikipedia

In fact, it is rather indispensable in many biochemical reactions in our bodies. Importantly, it is required in the production of energy in cells. NAD is a central component in a process of passing hydrogen electrons from one protein to another. In doing so, NAD transitions between NAD exists in two forms: an oxidized (NAD+) and reduced form (NADH – note the additional H – for hydrogen – on the bottom of the NADH in the image below).

NAD and NADH. Source: Wikipedia

This process is particularly essential for the continued production of energy in cells. That energy is called Adenosine Triphosphate.

What is Adenosine Triphosphate?

Adenosine Triphosphate (or ATP) is the unit of energy for your cells. It attaches to various proteins and ‘powers’ their function. It is produced by structures inside of cells called mitochondria.

Mitochondria. Source: Ohiostate

Mitochondria are tiny bean shaped objects that reside inside of almost every cell in your body. They function as the power stations of each cell and there are hundreds (often thousands) of them per cell, being moved around internally as needs dictate.

How do mitochondria supply the cell with energy?

Mitochondria convert nutrients (like glucose) from food into ATP.

Source: Mangomannutrition

A full explanation of the production of ATP is beyond the scope of this short post. To save space, I’m going to suggest you watch this video explainer of how mitochondria produce energy:

For those of you seeking more in-depth information of this process, I recommend watching this video:

For the sake of the rest of this post, it is simply important to understand that without NAD, the production of ATP starts to go wrong very quickly. NAD is present in every cell and it is essential for normal functioning.

Ok, got it. But what is nicotinamide riboside???

NAD itself is produced in two ways:

• a de novo pathway (the production of fresh NAD)
• a salvage pathway (the recycling of NAD)

The schematic below demonstrates what the production of NAD looks like on a basic level:

NAD production. Source: Wikipedia

On the left (aqua blue) side of this image is the de novo production pathway, while on the right (peach yellow) is the circular salvage pathway.

In the de novo route, an essential amino acid called ‘tryptophan‘ (Trp) is the starting point for the production of NAD. And this applies to the vast majority of vertebrates and single cell organism investigated thus far. Tryptophan is used in the body to make proteins and certain brain-signaling chemicals. In the production of NAD, it is converted into quinolate (QA), which is then converted to Nicotinic acid mononucleotide (NaMN).

Now one important detail with this initial pathway is that “and certain brain-signaling chemicals” part in the paragraph above. You see, tryptophan is also used in the production of the chemical serotonin (which is a neurotransmitter, like dopamine). Given the importance of both NAD and serotonin production, the body has a second method of producing NAD – and this is where Nicotinic acid (or niacin) comes into the story (you will remember out Norwegian friend Conrad Elvehjem at the top of the post discovered Nicotinic acid).

Nicotinic acid can also be used to produce Nicotinic acid mononucleotide (NaMN).

NaMN is then transferred to form nicotinic acid adenine dinucleotide (NaAD), which in turn is transforms nicotinamide adenine dinucleotide (NAD). And that is basic structure of the de novo production pathway:

NAD production. Source: Wikipedia

NAD is so critical for normal functioning, however, that cells can not rely solely on the de novo pathway for their essential supply. Thus, they have developed a system of recycling NDA, which is known as the ‘salvage pathway’.

On the salvage pathway, cells can recycle NAD and (as you can see on the right side of the image above) that involves the other of Conrad Elvehjem’s discoveries (Nicotinamide or Nam) and introduces nicotinamide riboside (or NR) into the cycling process.

Both nicotinamide (Nam) and nicotinamide riboside (NR) can be used to produce nicotinamide mononucleotide (NMN), which in turn can be converted into NAD. Nicotinamide riboside (NR) is converted to nicotinamide mononucleotide (NMN) by nicotinamide riboside kinase enzymes while nicotinamide (Nam) is converted into nicotinamide mononucleotide (NMN) by nicotinamide phosphoribosyltransferase (NAMPT).

And using these de novo and salvaging methods, a cell can keep itself supplied with NAD. If this process of NAD production is of interest to you, click here for a very good review of the topic.

Ok, enough of the biology lesson – let’s move on.

# RECAP #1: Nicotinamide adenine dinucleotide (or NAD) is a biomolecule that plays a role in many cellular functions. Importantly it helps in the production of Adenosine Triphosphate (or ATP), which is a unit of energy that is made in the mitochondria of cells. Nicotinamide riboside is a key ingredient in maintaining appropriate levels of NAD. #

Is there any research suggesting an associations between Parkinson’s and NAD processing?

Yes, there is.

Researchers have been investigating the effects of modulating the NAD pathway in neurotoxic models of Parkinson’s. For example, this study:

Title: NAMPT protects against 6-hydroxydopamine-induced neurotoxicity in PC12 cells through modulating SIRT1 activity
Authors: Zou XD, Guo SQ, Hu ZW, Li WL.
Journal: Mol Med Rep. 2016 May;13(5):4058-64.
PMID: 27035562

In this study, the scientists took two groups of cells and treated them with either an inhibitor of NAMPT (called FK866) or nicotinamide mononucleotide (NMN – the product of NAMPT activity). This resulted in the cells either having lower levels of NAD (with FK866 treatment) or higher levels of NAD (with NMN treatment). The researchers then treated the cells with a neurotoxin (6-OHDA) and observed what happened.

NMN treatment markedly reduced the negative effects of the neurotoxin, while FK866 treatment made the situation for the neurotoxin exposed cells a lot worse.

And this research is supported by similar results from an independent group of scientists:

Title: Nicotinamide mononucleotide improves energy activity and survival rate in an in vitro model of Parkinson’s disease.
Authors: Lu L, Tang L, Wei W, Hong Y, Chen H, Ying W, Chen S.
Journal: Exp Ther Med. 2014 Sep;8(3):943-950. Epub 2014 Jul 14.
PMID: 25120628                    (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers used a different neurotoxin (rotenone) but observed similar results by treating their cells with nicotinamide mononucleotide (NMN). Nicotinamide mononucleotide treatment protected the cells and restored NAD levels in the neurotoxin treated cells.

There has also been evidence that manipulating the NAD pathway could be beneficial in genetic forms of Parkinson’s:

Title: The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC and Fly Models of Parkinson’s Disease.
Authors: Schöndorf DC, Ivanyuk D, Baden P, Sanchez-Martinez A, De Cicco S, Yu C, Giunta I, Schwarz LK, Di Napoli G, Panagiotakopoulou V, Nestel S, Keatinge M, Pruszak J, Bandmann O, Heimrich B, Gasser T, Whitworth AJ, Deleidi M.
Journal: Cell Rep. 2018 Jun 5;23(10):2976-2988.
PMID: 29874584                   (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers were interested in the cellular response resulting from a genetic mutation in a region of DNA that is referred to as the GBA gene. We have previously discussed at length GBA and its association with Parkinson’s (Click here to read more about this).

The investigators collected skin cells from people with GBA genetic mutations and they converted those skin cells (or fibroblasts) into neurons via a trick of molecular biology. Those skin cells became induced pluripotent stem (or iPS) cells (which you can read about by clicking here). And these iPS cells can be encouraged to become any cell that you want, such as a neuron (or brain cell).

Making IPS cells. Source: learn.genetics

When the researchers compared the biology of the neurons derived from people with GBA genetic mutations with neurons from healthy control subjects, they found that the GBA cells had significant differences in their normal biology… beyond the usually reported lysosomal issues.

For example, they found that the GBA mutations were having an impact on the function of the mitochondria. The researchers reported that the cells carrying GBA mutation cells displayed mitochondria with morphological and functional defects.

Altered morphology in the GBA mitochondria. Source: Cell

The mitochondria in these cells also exhibited significantly reduced basal respiration and oxygen consumption rates, suggesting that the mitochondria were under performing in their energy production task.

When the researchers looked at NAD levels in the cells carrying GBA mutations, what do you think they found?

Any guesses?

No, not Jimmy Hoffer. Try again.

They found significant differences in the levels of key components of the NAD production process, suggesting that this pathway was disrupted in the cells from people with GBA-associated Parkinson’s.

Next, the investigators wanted to know if they could rescue some of these issues in the cells carrying GBA mutations. They started by treating normal control neurons with nicotinamide (NAM), nicotinamide mononucleotide (NMN), or nicotinamide riboside (NR), and then measuring NAD levels.

They found that nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) had the strongest effect in boosting NAD levels.

Given that nicotinamide riboside treatment has previous been shown to be safe in humans, the researchers focused their attention for the rest of their experiments on treating the cells carrying GBA mutations with nicotinamide riboside.

They found that nicotinamide riboside treatment significantly improved many aspects of mitochondria function. Remarkably, nicotinamide riboside treatment also increased levels of autophagy in the cells carrying GBA mutations. Autophagy being part of the waste disposal system of the cell.

And finally, the researchers wanted to test whether the response they were observing in cells could also be seen in living animals. They chose genetically engineered flies for this purpose:

Flies. Source: TheConservation

Flies carrying GBA genetic mutations suffer an age-dependent loss of dopamine neurons (similar to the situation in Parkinson’s in humans) and this cell loss is accompanied by progressive defects in the ability of the flies to climb. When the investigators treated flies carrying GBA mutations with nicotinamide riboside, they reported a significant reduction in the number of dopamine neuron dying, and a rescuing of climbing ability in the flies.

The scientists concluded their study by suggesting that nicotinamide riboside “may be a valuable therapeutic approach due to its high bioavailability, minimal toxicity, and evidence of its ability to cross the blood-brain barrier”. They also proposed that “future studies will explore the potential therapeutic benefits of combining NAD boosters with chaperones and GCase activators”.

(Hmmm, a combination of nicotinamide riboside and ambroxol???)

In addition to GBA, the NAD pathway has also been explored in the context of another Parkinson’s-associated gene – PINK1:

Title: Enhancing NAD+ salvage metabolism is neuroprotective in a PINK1 model of Parkinson’s disease<
Authors: Lehmann S, Loh SH, Martins LM.
Journal: Biol Open. 2016 Dec 23. pii: bio.022186.
PMID: 28011627              (this article is OPEN ACCESS if you would like to read it)

In this study, the researchers analysed flies with genetic mutations in the Parkinson’s associated PINK1 gene. They found that PINK1 mutant flies have decreased levels of NAD and they also exhibited problems with their mitochondria (Click here to read a previous post on PINK1 and mitochondria).

The researchers were curious to determine if a diet supplemented with nicotinamide (Nam) could help increase the production of NAD and rescue the mitochondrial defects observed in the PINK1 mutant fly. They fed the flies a diet high in Nam, and they found that not only did Nam rescue the mitochondrial problems in the flies, but it also protected neurons from degeneration.

Interestingly, reductions in NAD components have also been observed in the context of other Parkinson’s-associated genes, such as Parkin (Click here to read more about this) and LRRK2 (Click here to read more about this).

Interesting. What about the Parkinson’s-associated protein alpha synuclein?

For those readers unfamiliar with it, alpha synuclein is a protein that begins clumping together inside certain cells in many people with Parkinson’s (Click here to read more about alpha synuclein).

Back in 2013, some researchers discovered something rather interesting about NAD-associated proteins and their interactions with alpha synuclein. They reported their finding in this paper:

Title: NAD+ salvage pathway proteins suppress proteotoxicity in yeast models of neurodegeneration by promoting the clearance of misfolded/oligomerized proteins.
Authors: Ocampo A, Liu J, Barrientos A.
Journal: Hum Mol Genet. 2013 May 1;22(9):1699-708.
PMID: 23335597                  (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers used in yeast cells that produced high levels of NAD pathway components and they found that this manipulation protected the cells from alpha synuclein pathology (when the yeast cells were exposed to high levels of this protein). Their experiments suggested that the mechanism underlying this surprise effect “involves extensive clearance of the non-native protein“.

And very recently, the researchers have provided further data on this effect (Click here to read more about this). Based on these findings, the researchers have concluded “that the entire salvage NAD+ biosynthetic pathway links NAD+ metabolism and proteostasis and emerges as a target for therapeutics to combat age-associated neurodegenerative proteotoxicities“.

For those interested in reading more about NAD and neurodegenerative conditions, I highly recommend this review.

# # RECAP #2: Considerable preclinical research has demonstrated that manipulation of the NAD pathway can have beneficial effects on aspect of cellular activity (such as mitochondrial function and protein clearance). Reduced levels of NAD components has been observed in the context of different genetic forms of Parkinson’s. Enhancing the production of NAD rescues both neurotoxic and genetic models of Parkinson’s. # #

Has NAD manipulation ever been tested in Parkinson’s?

Very recently, some research in Norway published this report:

Title: The NADPARK study: A randomized phase I trial of nicotinamide riboside supplementation in Parkinson’s disease.
Authors: Brakedal B, Dölle C, Riemer F, Ma Y, Nido GS, Skeie GO, Craven AR, Schwarzlmüller T, Brekke N, Diab J, Sverkeli L, Skjeie V, Varhaug K, Tysnes OB, Peng S, Haugarvoll K, Ziegler M, Grüner R, Eidelberg D, Tzoulis C.
Journal: Cell Metab. 2022 Mar 1;34(3):396-407.e6.
PMID: 35235774                  (This report is OPEN ACCESS if you would like to read it)

In this study, a team of Norwegian researchers (and collaborators) – led by Prof Charalampos Tzoulis of Haukeland University Hospital – wanted to explore what nicotinamide riboside supplementation might do in the brains of people with Parkinson’s.

Prof Charalampos Tzoulis. Source: Ellines

They recruited 30 eligible individuals with Parkinson’s and randomly assigned them to either daily administration of 1000 mg of nicotinamide riboside (two 500mg pills taken 12 hours apart) or a placebo treatment for 30 days. They then assessed what was happening in the brains of these participants by analysing cerebrospinal fluid and conducting brain imaging (using ³¹P-MRS and FDG-PET – Click here to read more about the details of this study).

What on Earth is  ³¹P-MRS and FDG-PET?!?!?

³¹P-MRS (or ³¹phosphorous magnetic resonance spectroscopy) is a magnetic resonance-based form of imaging that is used to measure and quantify the function of the mitochondria. It will allow the researchers to assess whether the drug is successfully normalising the function of mitochondria in regions of the brain affected by Parkinson’s. For the participants the experience of ³¹P MRS will be exactly the same as having a normal MRI scan – you lie there in the machine thinking happy thoughts.

³¹P MRI-Spectroscopy. Source: PMC

¹⁸fluoro-deoxyglucose positron emission tomography (or FDG-PET) is another brain imaging technique, but this one measures the uptake and utilisation of glucose in the brain.

Ok, so what did they find?

Well, most importantly, the investigators found that orally-administered nicotinamide riboside was safe and well tolerated, PLUS it increased levels of NAD in the brain and in the blood of individuals with Parkinson’s.

Source: Cell

The researchers observed increases in markers of mitochondrial function and proteasomal function (part of the waste disposal system of cells). The participants who responded the most in terms of ³¹P MRS scores, actually exhibited altered cerebral metabolism, which was associated with mild clinical improvements (but it should be stressed here that this was a very small and short pilot study, and a much larger and longer study is required to make any proper determination of efficacy).

There were also indications that the treatment was reducing levels of markers of inflammation in both the blood and cerebrospinal fluid (this is the liquid that our brains sit in), which could have positive effects in the context of Parkinson’s.

Overall, the researchers felt that the results of their study were very encouraging and warrant further investigation in a much larger clinical trial.

So how long do we have to wait for that larger trial to start?

It already has.

Huh?!?

These same Norwegian researchers have already started the NOPARK study – a double-blind, randomised, placebo controlled, Phase 2 clinical study of 400 people with Parkinson’s that is assessing 1 year of daily nicotinamide supplementation in people recently diagnosed with PD. The participants enrolled in the study will be randomly assigned (using a 1:1 ratio) to either nicotinamide riboside or placebo, and clinically assessed at 4, 13, 26, 39 and 52 weeks (Click here to read more about this).

The study is scheduled to complete in mid-2024.

Wow! That’s great. Nicotinamide riboside sounds really interesting. Where can I get me some?

Nicotinamide riboside is a widely available supplement, but there is a small catch: it is rather pricey stuff.

A company called Chromadex controls the intellectual property (the patents) for production and use of nicotinamide riboside.

Most of those patents were awarded between 2010 and 2012 (they were originally issued to Dartmouth University, Cornell University, and Washington University). Chromadex bought the rights to those patents and started to sell nicotinamide riboside to suppliers under the label NIAGEN™ in 2013. They also now sell Niagen to customers under the label ‘Tru Niagen’.

In 2014, Chromadex started supplying other companies with nicotinamide riboside. One of those companies was called Elysium Health, which claimed to include nicotinamide riboside as an ingredient in their product Basis.

But this particular arrangement… um,… well, it turned kind of ugly… and then lawyers got involved… and it got even uglier!

There are blog posts all over the web describing this sad tale (Click here and here to learn about different levels of ugly). Chromadex has stopped supplying Elysium with Niagen, and it is unclear where Elysium is now acquiring their nicotinamide riboside.

If you are looking for a product that contains nicotinamide riboside, check the list of ingredients and make sure it contains wording something along the lines of “ChromaDex Inc.’s proprietary Nicotinamide Riboside ingredient, Niagen®. Niagen is a registered trademark of ChromaDex, Inc.”

Is Niagen safe?

Naigen has been tested to extremely high levels in rodents:

Title: Safety assessment of nicotinamide riboside, a form of vitamin B3
Authors: Conze DB, Crespo-Barreto J, Kruger CL.
Journal: Hum Exp Toxicol. 2016 Jan 20. pii: 0960327115626254.
PMID: 26791540

In this study, the researchers conducted 14-day and 90-day rat toxicology studies. The study basically looked at weight change in organs such as liver, kidneys and brain following treatment. There was also some more detailed (histological) analysis, but this did not include the brain. The lowest observed adverse effect level for Niagen was 1000 mg/kg/day, and no observed adverse effects were found at 300 mg/kg/day.

TWO IMPORTANT DETAILS TO NOTE HERE:

1. PLEASE DO NOT USE THOSE LEVELS OF NIAGEN AS A GUIDE AS THEY WERE CONDUCTED IN RODENTS.
2. NO ASSESSMENT OF NIAGEN IN THE BRAIN WAS MADE IN THIS STUDY (ONLY THE WEIGHT OF THE BRAIN WITH/WITHOUT TREATMENT WAS REPORTED).

More recently, a clinical study was conducted on healthy humans and this report was published:

Title: Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults.
Authors: Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR.
Journal: Nat Commun. 2018 Mar 29;9(1):1286.
PMID: 29599478                  (This report is OPEN ACCESS if you would like to read it)

In this study, the researchers conducted a 2 × 6-week randomised, double-blind, placebo-controlled crossover clinical study, in which participants ingested either Niagen (500 mg, twice per day) or a placebo for 6 weeks before being blindly shifted to the opposite treatment. The results suggest that Niagen was well tolerated and effectively at stimulating a 60% increase in NAD levels in the blood of healthy middle-aged and older adults (30 participants in total) when compared to placebo-treated levels.

Another (shorter) clinical study found similar results with Niagen treatment (Click here to read those results).

And there has also recently been a placebo-controlled, double-blinded clinical study, funded by the company Elysium, investigating the safety of their product Basis in 120 healthy older (60-80yrs) adults people has also been published. The participants who took the normal recommended dose of Basis for a month saw a 40 percent increase in their NAD blood levels. Those who took the higher dose (twice the recommended amount) saw a 90 percent boost (Click here to read the research report).

So what does it all mean?

Mitochondria are the energy producing power stations of cells. The biomolecule NAD is a key component of that energy production process, and recently researchers have been testing if oral treatment with a particular component of NAD production pathway can help to enhance mitochondrial function. They have found that nicotinamide riboside can increase energy levels in the brains of people with Parkinson’s in a small pilot study and they are now testing this agent in a longer term study to determine if it can impact the progression of the condition.

Mitochondrial dysfunction has long been associated with Parkinson’s, and we have been waiting to see if therapies that boost the function of this tiny cellular structures can help to slow down the progression of PD. A struggling mitochondria can cause a lot of cellular stress, which may make cells more vulnerable to additional stressors. Thus, improving the health of mitochondria represents a very compelling experimental therapeutic approach (see the mitochondria section of the 2022 Road Ahead post for additional agents targeting mitochondria).

An additional compelling feature of nicotinamide riboside is that if this treatment is found to be safe and well tolerated over a long period of time (such as 1 year in the ongoing NOPARK study discussed above), it will hopefully be a straightforward process to involving it in combinations with other agents that target additional aspect of Parkinson’s-associated biology (such as GCase activation or LRRK2 inhibition). For a long time readers have been asking when will the Parkinson’s field follow other areas of medical research and start investigating combination therapies. With progress in areas like nicotinamide riboside, GLP-1R agonists and other experimental approaches, we may soon be on the edge of combination approaches for Parkinson’s.

We will be watching the Norwegian NOPARK study very closely here at SoPD HQ.

 

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EDITOR’S NOTE: The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.

In addition, some of the companies mentioned in this post are publicly traded companies. That said, the material presented on this page should under no circumstances be considered financial advice. Any actions taken by the reader based on reading this material is the sole responsibility of the reader. None of the companies have requested that this material be produced, nor has the author had any contact with any of the companies or associated parties. This post has been produced for educational purposes only.

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